CN1723210A - Fused furan compound - Google Patents

Fused furan compound Download PDF

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Publication number
CN1723210A
CN1723210A CNA2004800019411A CN200480001941A CN1723210A CN 1723210 A CN1723210 A CN 1723210A CN A2004800019411 A CNA2004800019411 A CN A2004800019411A CN 200480001941 A CN200480001941 A CN 200480001941A CN 1723210 A CN1723210 A CN 1723210A
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amino
carbonyl
trans
pyridine
furo
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CN100344632C (en
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川口隆行
赤塚英则
饭嵨彻
渡边达也
村上润
三井隆志
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Mitsubishi Tanabe Pharma Corp
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Tanabe Seiyaku Co Ltd
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Abstract

The invention provides a fused furan compound represented by the formula (I): (I) wherein ring X represents benzene, pyridine, etc; Y represents optionally substituted amino, optionally substituted cycloalkyl, optionally substituted aryl, an optionally substituted saturated heterocyclic group, or an optionally substituted unsaturated heterocyclic group; A represents a single bond, lower alkylene, lower alkenylidene, lower alkenylene, or oxygen; R<1> represents hydrogen, halogeno, etc.; R<3> represents hydrogen, etc.; and R<4> represents hydrogen, etc., or a pharmacologically acceptable salt of the compound. The compounds are useful as a medicine, especially an inhibitor against an activated blood coagulation factor X.

Description

The condensed furan compound
Technical field
The present invention relates to a kind of medicament that can be used as, particularly as the condensed furan compound of activatory blooc coagulation factor X inhibitor, perhaps its pharmacy acceptable salt.
Background technology
In recent years, the westization of living habit and aging population subsequently, thromboembolism class disease, for example myocardial infarction, cerebral infarction and peripheral arterial thrombosis form, and increase year by year, and the social importance of its treatment is more and more higher.
In the thromboembolism class treatment of diseases, anticoagulant treatment and solution fibrin treatment and Antiplatelet therapy are the parts for the treatment of and preventing thrombotic pharmacotherapy.(Sogorinsho41：2141-2145，1989)。Particularly safety long term administration constantly, and active reliable and suitable expression of anticoagulant is that the prevention thrombosis is necessary.Coumarin derivatives, particularly trombolysan potassium as unique anticoagulant that can be oral, often use in the whole world.But owing to the characteristic that its mechanism of action produces, its drug effect needs just can show for a long time, although the concentration range relative narrower of performance drug effect, its transformation period in blood is very long, and effective dose also shows tangible individual difference.Therefore, its anticoagulant active is difficult to control (Journalof Clinical Pharmacology, 1992, the 32 volumes, 196-209 page or leaf; NEW ENGLANDJOURNAL OF MEDICINE, 1991, the 324 volumes, 26 phases, 1865-1875 page or leaf).In addition, also have adverse drug reaction, danger such as hemorrhage, nausea,vomiting,diarrhea, depilation are for example arranged, therefore, its clinical application is unusual difficulty, need develop useful and the easy to handle anticoagulant.
The enhancing of blood coagulation ability in addition, is a significant causative factor of the thrombosis in obturation and the extracorporeal circulation process etc. again after unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, lung infraction, pulmonary infarction, Burger disease, venous thrombosis, disseminated intravascular coagulation, prosthetic heart valve are transplanted back thrombosis, blood circulation and rebuild.Therefore, wish to have have good dose response, low hemorrhage risk, almost be free from side effects, and by the oral remarkable anticoagulant (Thrombosis Research, 1992, the 68 volumes, 507-512 page or leaf) that can bring into play enough effects.
Zymoplasm has not only participated in the Fibrinogen of blood coagulation chain reaction final stage to fibrinous conversion, and hematoblastic activation and cohesion (Matsuo have deeply been participated in, O., " t-PA andPro-UK ", Gakusaikikaku, 1986, the 5-40 page or leaf), its inhibitor is the center of anticoagulant research as the target of new drug development for a long time always.But, the bioavailability of oral thrombin inhibitors is low, and also has the shortcoming of security aspect, for example an one side effect is that bleeding tendency (Biomedica Biochimica Acta is arranged, 1985, the 44 volumes, the 1201-1210 page or leaf), up to now, also do not have on the market can be oral thrombin inhibitors.
Activatory blooc coagulation factor X is that external and intrinsic solidify a kind of key enzyme in the chain reaction common pathway.Xa factor is positioned at the upstream of zymoplasm in solidifying chain reaction.Therefore, suppress Xa factor and compare with Trombin inhibiting, may more effective and single-minded (Thrombosis Research, 1980, the 19 roll up the 339-349 page or leaf) in the inhibition of coagulation system.
Therefore, expect for a long time the anticoagulant active that suppresses blooc coagulation factor Xa and demonstrate the material of outstanding enzyme selectivity and high bioavailability is controlled always, and can show the result of treatment better than existing anticoagulant by oral.Therefore, earnestly need develop the new inhibitor (FXa inhibitor) of activation blooc coagulation factor X that can be oral.
Having inhibiting known compound example to comprise to activation blooc coagulation factor X can be used for prevention or treats thrombotic thiobenzoyl amine compound (WO99/42439).
Following benzofuran compound is known (Indian Journal of HeterocyclicChemistry, 1994, the 3 volumes, 3247-3252 page or leaf), but the document is not mentioned the restraining effect of these compounds to activatory blooc coagulation factor X.
Figure A20048000194100171
The condensed-bicyclic amide compound of following formula:
Have the activity that suppresses the activated lymphocyte growth, can be used as the medicine of prevention or treatment autoimmune disorder, these compounds are known (WO02/12189).But WO02/12189 does not mention the restraining effect of these compounds to activatory blooc coagulation factor X yet.Disclose the condensed ring that contains pyridine and furans in the literary composition, the acid amides and the formamyl that are connected on this ring are replaced by two; But phenyl ring all is connected on the nitrogen-atoms of formamyl in all these compounds, and is replaced by X and Y simultaneously.
Summary of the invention
The invention provides activatory blooc coagulation factor X is had fabulous inhibiting novel fused furan compound, perhaps its pharmacy acceptable salt.
The present inventor finds that the furan compound that condenses of following general formula has fabulous restraining effect to activatory blooc coagulation factor X, thereby has finished the present invention through broad research.
That is, the present invention is as follows:
1, a kind of general formula (I) condense furan compound:
Wherein, ring:
Be
Perhaps
Ring X is:
Figure A20048000194100192
Perhaps
Y is the optional amino that replaces; The optional cycloalkyl that replaces; The optional aryl that replaces; The optional saturated heterocyclyl that replaces; The perhaps optional unsaturated heterocycle base that replaces;
A is a singly-bound; The optional alkylidene group that is replaced by the oxo base; Alkene support base (alkenylene); Alkenylene (alkenylidene); Perhaps Sauerstoffatom;
R 1A, R 1BBe identical or different groups, the hydrogen of respectively doing for oneself; Halogen; Alkyl; Haloalkyl; Alkoxyl group; Cyano group; Nitro; The perhaps optional amino that replaces;
R 1CBe hydrogen, alkyl or halogen;
R 2A, R 2BBe identical or different groups, the hydrogen of respectively doing for oneself; Halogen; The optional alkyl that replaces; The optional alkoxyl group that replaces; The optional amino that replaces; Nitro; Cyano group; Hydroxyl; Carboxyl; The optional carbalkoxy that replaces; The optional formamyl that replaces; The carbonyl that the saturated heterocyclyl that is optionally substituted replaces; The optional saturated heterocyclyl that replaces; Aryl; The perhaps optional unsaturated heterocycle base that replaces;
R 3Be hydrogen or alkyl; And
R 4Be hydrogen or alkyl,
Perhaps its pharmacy acceptable salt.
2, according to 1 the furan compound that condenses, ring wherein:
Be
Figure A20048000194100201
Figure A20048000194100202
Perhaps
Figure A20048000194100203
Definition is identical in the symbol wherein and top 1,
Perhaps its pharmacy acceptable salt.
3, according to 1 or 2 the furan compound that condenses, ring wherein:
Figure A20048000194100204
Be
Perhaps
Definition is identical in the symbol wherein and top 1,
Perhaps its pharmacy acceptable salt.
4, according to 1-3 any one condense furan compound, wherein Y is optional cycloalkyl that replaces or the optional saturated heterocyclyl that replaces,
Perhaps its pharmacy acceptable salt.
5, according to above-mentioned 1-4 any one condense furan compound, be to be selected from the optional alkyl that replaces wherein to the substituting group in " the optional cycloalkyl that replaces " definition of Y; The optional formamyl that replaces; The carbonyl that the saturated heterocyclyl that is optionally substituted replaces; The optional amino that replaces; With a kind of group of the optional saturated heterocyclyl that replaces,
Perhaps its pharmacy acceptable salt.
6, according to above-mentioned 1-5 any one condense furan compound, be a kind of group that is selected from following group to the substituting group in " the optional cycloalkyl that replaces " definition of Y wherein: the group that (1) is selected from the optional acyl group that replaces, carbalkoxy and the optional alkyl that replaces choose the amino of replacement; (2) group that is selected from optional acyl group that replaces and the optional alkyl that replaces is chosen the aminoalkyl group that replaces wantonly; (3) alkyl that is optionally substituted is chosen the formamyl that replaces wantonly; (4) carbonyl that is replaced by saturated heterocyclyl; (5) the optional saturated heterocyclyl that replaces,
Perhaps its pharmacy acceptable salt.
7, according to above-mentioned 5 or 6 the furan compound that condenses, wherein saturated heterocyclyl is 4 yuan of-7 yuan of saturated heterocyclyls, and this heterocyclic radical comprises 1-4 the heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom,
Perhaps its pharmacy acceptable salt.
8, according to above-mentioned 5-7 any one condense furan compound, wherein saturated heterocyclyl is a kind of group that is selected from imidazolidyl, pyrazolidyl, piperidyl, piperidino-(1-position only), piperazinyl, (2-or 3-) morpholinyl, morpholino, thio-morpholinyl, thiomorpholine generation, high piperazinyl, homopiperidinyl, high-piperidine sub-base and pyrrolidyl
Perhaps its pharmacy acceptable salt.
9, according to above-mentioned 1-6 any one condense furan compound, wherein be: the amino that (1) optional a kind of group that is selected from aminoalkyl group, alkoxycarbonyl amido alkyl and amidoalkyl that acyl group, carbalkoxy, alkyl, aminoalkyl group, alkyl replace replaces to the substituting group in " the optional cycloalkyl that replaces " definition of Y; (2) by the amino alkyl that replaces, wherein amino choosing wantonly replaced by alkyl; (3) optional by alkyl or aminoalkyl group one replacement or dibasic formamyl, wherein aminoalkyl group can be replaced by alkyl; (4) be selected from a kind of group of pyrrolidyl carbonyl, piperidino carbonyl, piperazinyl carbonyl, morpholino carbonyl, homopiperidinyl carbonyl and high piperazinyl carbonyl; Perhaps (5) are selected from the saturated heterocyclyl of the optional pyrrolidyl that is replaced by the oxo base, the optional piperidyl that is replaced by the oxo base, the optional piperazinyl that is replaced by the oxo base, the optional morpholino base that is replaced by the oxo base, the optional homopiperidinyl that is replaced by the oxo base and the optional high piperazinyl that is replaced by the oxo base
Perhaps its pharmacy acceptable salt.
10, according to above-mentioned 1-6 any one condense furan compound, be the optional pyrrolidyl that is replaced by the oxo base wherein to the substituting group in " the optional cycloalkyl that replaces " definition of Y; The optional morpholino base that is replaced by the oxo base; The dialkyl amido formyl radical; The pyrrolidyl carbonyl; By alkyl and the disubstituted amino of amidoalkyl; Perhaps dialkyl amido,
Perhaps its pharmacy acceptable salt.
11, according to above-mentioned 1-3 any one condense furan compound, wherein Y is aryl or the undersaturated heterocyclic radical that the formamyl that is optionally substituted replaces,
Perhaps its pharmacy acceptable salt.
12, according to above-mentioned 1-11 any one condense furan compound, wherein A is singly-bound or methylene radical,
Perhaps its pharmacy acceptable salt.
13, according to above-mentioned 1-4 any one condense furan compound, wherein A is singly-bound or methylene radical, Y is optional unsaturated heterocycle base or the saturated heterocyclyl that is replaced by alkyl,
Perhaps its pharmacy acceptable salt.
14, according to above-mentioned 1-3 any one condense furan compound, wherein A is a tetramethylene, Y is the optional saturated heterocyclyl that replaces, perhaps its pharmacy acceptable salt.
15, according to above-mentioned 1-14 any one condense furan compound, wherein R 1A, R 1BBe identical or different groups, the hydrogen of respectively doing for oneself, halogen or alkyl,
Perhaps its pharmacy acceptable salt.
16, according to above-mentioned 1-15 any one condense furan compound, wherein R 2A, R 2BBe identical or different groups, the hydrogen of respectively doing for oneself; Halogen; The optional alkyl that replaces; The optional alkoxyl group that replaces; The optional amino that replaces; Cyano group; Carboxyl; Carbalkoxy; The optional formamyl that replaces; The carbonyl that is replaced by saturated heterocyclyl; Perhaps saturated heterocyclyl,
Perhaps its pharmacy acceptable salt.
17, according to above-mentioned 16 the furan compound that condenses, wherein saturated heterocyclyl is 4 yuan of-7 yuan of saturated heterocyclyls, and this heterocyclic radical comprises 1-4 the heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, perhaps its pharmacy acceptable salt.
18, according to above-mentioned 1-17 any one condense furan compound, wherein R 2A, R 2BIt is identical or different groups; respectively do for oneself hydrogen, fluorine, chlorine, bromine, methyl, methylol, methoxyl group, amino, sulfonyloxy methyl amino, kharophen, t-butoxycarbonyl amino, dimethylamino, cyano group, carboxyl, methoxycarbonyl, ethoxycarbonyl, methoxyl group, oxyethyl group, isopropoxy, methoxyethoxy, formyl-dimethylamino, N-methyl-N-(2-methoxyethyl) formamyl, pyrrolidyl, pyrrolidyl carbonyl, morpholino carbonyl or morpholino
Perhaps its pharmacy acceptable salt.
19, according to above-mentioned 1-18 any one condense furan compound, wherein R 3Be hydrogen, perhaps its pharmacy acceptable salt.
20, according to above-mentioned 1-19 any one condense furan compound, wherein R 4Be hydrogen, perhaps its pharmacy acceptable salt.
21, according to above-mentioned 1-20 any one condense furan compound, wherein encircle X and be
Figure A20048000194100231
Figure A20048000194100232
Perhaps
Definition is identical in the symbol wherein and top 1,
Perhaps its pharmacy acceptable salt.
22,, wherein encircle X and be according to above-mentioned 21 the furan compound that condenses
Figure A20048000194100234
Perhaps
Definition is identical in the symbol wherein and top 1,
Perhaps its pharmacy acceptable salt.
23, according to above-mentioned 1-22 any one condense furan compound, this compound is selected from following compound:
(1) 5-amino-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(2) 6-amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(3) N-(4-chloro-phenyl-)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(4) amino N-(5-chloropyridine-2-yl)-5-[(methylsulfonyl)]-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-2-carboxamide,
(5) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-5-carboxylic acid,
(6) N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-base-cyclohexyl) carbonyl] amino furo [3,2-c] pyridine-2-carboxamide,
(7) N-(5-chloropyridine-2-yl)-5-(methylol)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(8) N-(5-chloropyridine-2-yl)-5-methoxyl group-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(9) N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-base-cyclohexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(10) N-(5-chloropyridine-2-yl)-5-methoxyl group-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(11) N-(4-chloro-phenyl-)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(12) 5-amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(13) 5-(kharophen)-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(14) N-(5-chloropyridine-2-yl)-5-fluoro-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(15) 5-chloro-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(16) N-(5-chloropyridine-2-yl)-5-methyl-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(17) N 2-(5-chloropyridine-2-yl)-N 5, N 5-dimethyl-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-2, the 5-diformamide,
(18) 5-(kharophen)-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(19) (2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-6-yl)-t-butyl carbamate,
(20) amino N-(5-chloropyridine-2-yl)-5-[(methylsulfonyl)]-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(21) N-(4-chloro-phenyl-)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl)-cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(22) carbonyl N-(5-chloropyridine-2-yl)-3-{[(1-pyridin-4-yl piperidin-4-yl)] amino } furo [3,2-b] pyridine-2-carboxamide,
(23) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(24) [2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-6-yl] t-butyl carbamate,
(25) 6-amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(26) 6-amino-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(27) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylic acid,
(28) N 2-(5-chloropyridine-2-yl)-N 5, N 5-dimethyl-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2, the 5-diformamide,
(29) N-(5-chloropyridine-2-yl)-5-(morpholine-4-base carbonyl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(30) (2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-5-yl)-t-butyl carbamate,
(31) N-(5-chloropyridine-2-yl)-5-methyl-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(32) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-5-carboxylate methyl ester,
(33) 5-bromo-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(34) amino N-(5-chloropyridine-2-yl)-5-[(methylsulfonyl)]-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(35) N-(4-chloro-phenyl-)-3-({ [trans-4-(dimethylamino) cyclohexyl]-carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(36) N-(5-chloropyridine-2-yl)-5-cyano group-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(37) N-(5-chloropyridine-2-yl)-5-fluoro-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(38) N 2-(5-chloropyridine-2-yl)-N 5-(2-methoxyethyl)-N 5-methyl-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2, the 5-diformamide,
(39) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(40) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino)-5-(tetramethyleneimine-1-base carbonyl) furo [3,2-b] pyridine-2-carboxamide,
(41) [2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-yl] t-butyl carbamate,
(42) 5-bromo-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(43) N-(5-chloropyridine-2-yl)-5-(morpholine-4-base carbonyl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(44) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-5-methoxyl group furo [3,2-b] pyridine-2-carboxamide,
(45) 5-chloro-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl) carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(46) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylic acid,
(47) N-(5-chloropyridine-2-yl)-5-cyano group-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(48) N-(5-chloropyridine-2-yl)-5-cyano group-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(49) N-(5-chloropyridine-2-yl)-5-(methylol)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(50) N-(5-chloropyridine-2-yl)-5-methoxyl group-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(51) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino)-5-(tetramethyleneimine-1-base carbonyl) furo [3,2-b] pyridine-2-carboxamide,
(52) N-(5-chloropyridine-2-yl)-5-methyl-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(53) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-5-methyl furan [3,2-b] pyridine-2-carboxamide also,
(54) 5-chloro-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(55) N 2-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-N 5, N 5-dimethyl furan is [3,2-b] pyridine-2 also, the 5-diformamide,
(56) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylate methyl ester,
(57) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(58) 5-amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(59) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(60) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-{[5-(3-oxo morpholine-4-yl) pentanoyl] amino } furo [3,2-b] pyridine-5-carboxylic acid,
(61) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(62) 6-chloro-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(63) 5-chloro-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(64) N 2-(5-chloropyridine-2-yl)-N 5, N 5-dimethyl-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2, the 5-diformamide,
(65) 6-(kharophen)-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(tetramethyleneimine-1-basic ring hexyl) carbonyl] amino } furo [3,2-b] pyridine-2-carboxamide,
(66) [2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-6-yl] t-butyl carbamate,
(67) 6-chloro-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(68) N-(4-aminomethyl phenyl)-3-({ [trans-4-(3-oxo morpholine-4-yl)-cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(69) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-6-carboxylic acid,
(70) N-(5-chloropyridine-2-yl)-3-{[5-(3-oxo morpholine-4-yl) pentanoyl] amino } furo [3,2-b] pyridine-2-carboxamide,
(71) 5-(kharophen)-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(72) N-(4-chloro-phenyl-)-3-{[(trans-4-morpholine-4-basic ring hexyl)-carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(73) 5-bromo-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(74) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino) furo [2,3-b] pyridine-2-carboxamide,
(75) 3-[({ trans-4-[[3-(kharophen) propyl group] (methyl) amino]-cyclohexyl carbonyl) amino]-N-(5-chloropyridine-2-yl) furo [3,2-b] pyridine-2-carboxamide,
(76) trans-N '-(2-{[(5-chloropyridine-2-yl) amino] carbonyl } furo [3,2-b] pyridin-3-yl)-N, N-dimethyl cyclohexane-1, the 4-diformamide,
(77) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(tetramethyleneimine-1-base carbonyl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(78) 2-{ ((5-chloropyridine-2-yl) amino] carbonyl }-3-[({ is trans-the 4-[(dimethylamino) carbonyl] cyclohexyl carbonyl) amino] furo [3,2-b]-pyridine-5-carboxylic acid,
(79) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-({ [trans-4-(tetramethyleneimine-1-base carbonyl) cyclohexyl] carbonyl } amino) furo [3,2-b]-pyridine-5-carboxylate methyl ester,
(80) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-the trans 4-[(dimethylamino of 3-[({) carbonyl] cyclohexyl } carbonyl) amino] furo [3,2-b] pyridine-5-carboxylate methyl ester,
(81) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-({ [trans-4-(tetramethyleneimine-1-base carbonyl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylic acid,
(82) N 2-(5-chloropyridine-2-yl)-3-[({ is trans-the 4-[(dimethylamino)-carbonyl] cyclohexyl } carbonyl) amino]-N 5-(2-methoxyethyl)-N 5-methyl furan is [3,2-b] pyridine-2 also, the 5-diformamide,
(83) N 2-(5-chloropyridine-2-yl)-N 5-(2-methoxyethyl)-N 5-methyl-3-({ [trans-4-(tetramethyleneimine-1-base carbonyl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2, the 5-diformamide,
(84) N-(5-chloropyridine-2-yl)-5-tetramethyleneimine-1-base-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(85) N-(5-chloropyridine-2-yl)-5-morpholine-4-base-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(86) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino)-5-tetramethyleneimine-1-base furo [3,2-b] pyridine-2-carboxamide,
(87) N-(5-chloropyridine-2-yl)-5-(dimethylamino)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(88) N-(5-chloropyridine-2-yl)-5-morpholine-4-base-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(89) N-(5-chloropyridine-2-yl)-4-(2-methoxyethoxy)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-c] pyridine-2-carboxamide,
(90) N-(5-chloropyridine-2-yl)-5-(2-methoxyethoxy)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(91) N-(5-chloropyridine-2-yl)-5-(tetramethyleneimine-1-base carbonyl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(92) N-(5-chloropyridine-2-yl)-4-(2-methoxyethoxy)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(93) N-(5-chloropyridine-2-yl)-4-methoxyl group-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-c] pyridine-2-carboxamide,
(94) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-5-tetramethyleneimine-1-base furo [3,2-b] pyridine-2-carboxamide,
(95) N 2-(5-chloropyridine-2-yl)-N 5-(2-methoxyethyl)-N 5-methyl-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-2, the 5-diformamide,
(96) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(97) N-(5-chloropyridine-2-yl)-5-(dimethylamino)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(98) N-1H-indoles-6-base-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(99) N-(5-chloropyridine-2-yl)-4-methoxyl group-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(100) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino)-5-tetramethyleneimine-1-base furo [3,2-b] pyridine-2-carboxamide,
(101) N-(5-chloropyridine-2-yl)-5-isopropoxy-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(102) N-(5-chloropyridine-2-yl)-5-isopropoxy-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(103) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino) cyclohexyl] carbonyl } amino)-5-(2-methoxyethoxy)-furo [3,2-b] pyridine-2-carboxamide,
(104) N-(5-chloropyridine-2-yl)-5-morpholine-4-base-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(105) N-(5-chloropyridine-2-yl)-5-(dimethylamino)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(106) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-5-morpholine-4-base furo [3,2-b] pyridine-2-carboxamide,
(107) N-(5-chloropyridine-2-yl)-5-(2-methoxyethoxy)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(108) N-(5-chloropyridine-2-yl)-5-(dimethylamino)-3-({ [trans-4-(dimethylamino) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(109) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-5-isopropoxy furo [3,2-b] pyridine-2-carboxamide,
(110) N-1H-indoles-6-base-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(111) N-(5-chloropyridine-2-yl)-4-cyano group-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-c] pyridine-2-carboxamide,
(112) N-(5-chloropyridine-2-yl)-4-methyl-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(113) N-(5-chloropyridine-2-yl)-4-cyano group-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(114) N-(5-chloropyridine-2-yl)-4-methyl-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(115) 4-chloro-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide and
(116) N-(5-chloropyridine-2-yl)-4-methyl-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-c] pyridine-2-carboxamide,
Perhaps its pharmacy acceptable salt.
24, the compound of general formula (II):
Figure A20048000194100311
What wherein define in the symbol and top 1 is identical, perhaps its salt.
25, the compound of general formula (VI):
Figure A20048000194100312
What wherein define in the symbol and top 1 is identical, perhaps its salt.
26, the compound of general formula (IV):
Figure A20048000194100321
Wherein R is a hydrogen, C 1-4Alkyl or carboxyl-protecting group, definition is identical in other symbols and top 1, perhaps its salt.
27, the compound of general formula (IX):
Figure A20048000194100322
Wherein R is a hydrogen, C 1-4Alkyl or carboxyl-protecting group, definition is identical in other symbols and top 1, perhaps its salt.
The present invention also comprises following invention.
28, a kind of medicament that comprises general formula (I) compound or its pharmacy acceptable salt.
29, a kind of inhibitor that activates blooc coagulation factor X, this inhibitor comprise general formula (I) compound or its pharmacy acceptable salt as activeconstituents.
30, according to the inhibitor of above-mentioned 29 activation blooc coagulation factor X, this inhibitor is a kind of medicament that is used to prevent or treat the obstacle that is caused by thrombus and/or embolus.
31; the inhibitor of activation blooc coagulation factor X according to above-mentioned 30; wherein the obstacle that is caused by thrombus and/or embolus is selected from: stablize stenocardia; unstable angina; cerebral thrombosis; cerebral infarction; cerebral embolism; transient ischemic attack (TIA); ischemic cerebrovascular; the cerebral vasospasm after the subarachnoid hemorrhage for example; the ischemic heart disease that causes by Coronary thrombosis; congested chronic heart failure; myocardial infarction; acute myocardial infarction; the lung infraction; pulmonary infarction; pulmonary vascular disease; economic class syndromes; kidney disease (diabetic kidney disease; chronic glomerulonephritis; IgA nephropathy etc.); the thrombosis of atherosclerosis association (thrombogenesis withatherosclerosis); periphery artery occlusion; the peripheral vein obturation; the Burger disease; venous thrombosis; disseminated intravascular coagulation (DIC); thrombosis after replace in synthetic vascular prosthesis transplanting or prosthetic heart valve or joint; intermittent claudication; thrombosis after blood circulation is rebuild and inaccessible again, for example thrombosis after the logical again art (PTCR) and inaccessible again in percutaneous tranluminal coronary angioplasty (PTCA) or the percutaneous coronary chamber; systemic inflammatory reaction syndromes (SIRS); multiple organ dysfunction syndrome (MODS); thrombosis in the extracorporeal circulation; blood coagulation under blood drawing (blooddrawing) situation; diabetic cycle penalty; transplant rejection; function under Organoprotective and the transplanting situation is improved.
32, a kind of pharmaceutical composition, said composition comprise compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of general formula (I).
The substituting group of each symbol representative that uses in this specification sheets and the claim will be described below.
(1) the substituting group example in " the optional amino that replaces " definition of Y is being comprised the optional alkyl that replaces, the optional saturated heterocyclyl that replaces, acyl group etc.Wherein, alkyl, optional piperidyl or the acyl group that is replaced by alkyl are preferred.
Herein, term " alkyl " implication is, for example, contains the straight or branched alkyl of 1-6 carbon atom, is in particular methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.Wherein, C 1-4Alkyl is preferred.
The example of " the optional piperidyl that is replaced by alkyl " comprise optional contained 1-6 carbon atom, preferably contain the piperidyl of the straight or branched alkyl replacement of 1-4 carbon atom, be specially piperidin-4-yl, 1-methyl piperidine-4-base, 1-ethyl piperidine-4-base, 1-sec.-propyl piperidin-4-yl etc.
The example of " acyl group " comprises alkyloyl, alkyl thiocarbonyl and alkyl sulphonyl.Term " alkyloyl " is meant, for example, contains the straight or branched alkyloyl of 1-6 carbon atom, is specially formyl radical, ethanoyl, propionyl, butyryl radicals etc.Term " alkyl thiocarbonyl " is meant, for example, contains the straight or branched alkyl thiocarbonyl of 2-6 carbon atom, is specially ethanethioyl, sulfo-propionyl etc.Term " alkyl sulphonyl " is meant, for example, contains the straight or branched alkyl sulphonyl of 1-6 carbon atom, is specially methylsulfonyl, ethylsulfonyl etc.
(2) " optional replace cycloalkyl " example of Y comprises and can contain substituent cycloalkyl; substituting group is for example: (a) the optional alkyl that replaces; (b) the optional formamyl that replaces; (c) carbonyl that the saturated heterocyclyl that is optionally substituted replaces; (d) choose the amino that replaces wantonly, (e) choose the saturated heterocyclyl of replacement etc. wantonly.The example of " cycloalkyl " comprises C 3-7Cycloalkyl be specially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc., and cyclohexyl is preferred.
(a) herein, term " the optional alkyl that replaces " is meant optional by the amino alkyl that replaces, and described amino can have one or two to be selected from the substituting group of acyl group and alkyl.Term " alkyl " is meant, for example, contains the straight or branched alkyl of 1-6 carbon atom, is specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.
Comprise alkyloyl, alkyl thiocarbonyl and alkyl sulphonyl as substituent " acyl group " example.Term " alkyloyl " is meant, for example, contains the straight or branched alkyloyl of 1-6 carbon atom, is specially formyl radical, ethanoyl, propionyl, butyryl radicals etc.Term " alkyl thiocarbonyl " is meant, for example, contains the straight or branched alkyl thiocarbonyl of 2-6 carbon atom, is specially ethanethioyl, sulfo-propionyl etc.Term " alkyl sulphonyl " is meant, for example, contains the straight or branched alkyl sulphonyl of 1-6 carbon atom, is specially methylsulfonyl, ethylsulfonyl etc.
Comprise the straight or branched alkyl that contains 1-6 carbon atom as substituent " alkyl ", be specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.
In " the optional alkyl that replaces ", preferably be selected from the optional acyl group that replaces and chosen wantonly the aminoalkyl group that replaces, the more preferably aminoalkyl group that is replaced by alkyl with the optional alkyl that replaces.
The specific examples of " optional replace alkyl " comprise aminomethyl, the methyl aminomethyl, dimethylaminomethyl, ethyl aminomethyl, diethyl amino methyl, diethyl aminoethyl, ethanoyl aminomethyl, the propionyl aminomethyl, N-ethanoyl-N-methyl aminomethyl etc.
(b) term " the optional formamyl that replaces " is meant and can contains the optional alkyl that replaces as substituent formamyl.
Comprise the straight or branched alkyl that contains 1-6 carbon atom as substituent " alkyl " example, be specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc., and methyl and ethyl are particularly preferred.Alkyl can be replaced by following groups: amino, this amino is optional by C 1-4Alkyl one or two replaces; Hydroxyl; Perhaps C 1-4Alkoxyl group, for example amino, methylamino-, dimethylamino, diethylamino, hydroxyl, methoxyl group, oxyethyl group etc.The specific examples of substituted alkyl comprises aminoethyl, methyl aminoethyl, dimethylaminoethyl, hydroxyethyl, hydroxypropyl, methoxyethyl, ethoxyethyl, methoxycarbonyl propyl etc.
The specific examples of " the optional formamyl that replaces " comprises formamyl, formyl-dimethylamino, diethylamino formyl radical, N-ethyl-N-methylamino formyl radical, N-methyl-N-(2-hydroxyethyl) formamyl, N-methyl-N-(2-methoxyethyl) formamyl, N-methyl-N-(2-dimethyl aminoethyl) formamyl, N-ethyl-N-(2-dimethyl aminoethyl) formamyl etc.
(c) term " carbonyl that the saturated heterocyclyl that is optionally substituted replaces " is meant, for example, involved 1-4, the carbonyl that 5 yuan of-7 yuan of saturated heterocyclyls of preferred 1 or 2 heteroatomic optional replacement that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom replace is specially imidazolidyl carbonyl, pyrazolidyl carbonyl, piperidino carbonyl, piperidino-(1-position only) carbonyl, piperazinyl carbonyl, morpholinyl carbonyl, morpholino carbonyl, thio-morpholinyl carbonyl, thiomorpholine for carbonyl, high piperazinyl carbonyl, homopiperidinyl carbonyl, high-piperidine sub-base carbonyl, pyrrolidyl carbonyl etc.Preferred embodiment comprises pyrazolidyl carbonyl, piperidino carbonyl, piperidino-(1-position only) carbonyl, piperazinyl carbonyl, morpholino carbonyl, high-piperidine sub-base carbonyl, high piperazinyl carbonyl etc.Saturated heterocyclyl can be replaced by following group: the optional C that replaces 1-4Alkyl (C 1-4The substituting group of alkyl: optional by C 1-4Alkyl one replacement or dibasic amino, C 1-4Alkoxyl group, hydroxyl etc.); Can be by C 1-4Alkyl one replaces or dibasic amino; C 1-4Alkoxyl group; Hydroxyl; Oxo base etc.
(d) term " is chosen the amino that replaces wantonly " and is meant and for example can have the substituent amino that (i) chooses the acyl group that replaces, the alkyl of (ii) carbalkoxy, (iii) optional replacement etc. wantonly.
(i) comprise alkyloyl, alkyl thiocarbonyl and alkyl sulphonyl herein, as the example of substituent " optional replace acyl group ".Term " alkyloyl " is meant, for example, contains the straight or branched alkyloyl of 1-6 carbon atom, is specially formyl radical, ethanoyl, propionyl, butyryl radicals etc.Term " alkyl thiocarbonyl " is meant, for example, contains the straight or branched alkyl thiocarbonyl of 2-6 carbon atom, is specially ethanethioyl, sulfo-propionyl etc.Term " alkyl sulphonyl " is meant, for example, contains the straight or branched alkyl sulphonyl of 1-6 carbon atom, is specially methylsulfonyl, ethylsulfonyl etc.Acyl group can be by saturated heterocyclyl (pyrrolidino, piperidino-(1-position only), morpholino, piperazine-1-base etc.), optional by C 1-6Acyl group or C 1-6The replacements such as amino that alkyl replaces.
(ii) the example as substituent " carbalkoxy " comprises the straight or branched carbalkoxy that contains 2-7 carbon atom, is specially methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl etc.
(iii) the example as substituent " the optional alkyl that replaces " comprises the straight or branched alkyl that contains 1-6 carbon atom, is specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.Alkyl can have the substituting group that is selected from hydroxyl, optional amino, carbalkoxy, cyano group and the saturated heterocyclyl that replaces.In these substituting groups, " the optional amino that replaces " is meant and can be selected from C 1-6Alkyl, C 1-6Acyl group and C 2-71 or 2 substituent amino of carbalkoxy, its specific examples comprises amino, methylamino-, dimethylamino, diethylamino, formamido group, kharophen, N-ethanoyl-N-methylamino-, N-formyl radical-N-methylamino-, N-ethanoyl-N-ethylamino, methoxycarbonyl amino, t-butoxycarbonyl amino etc.Term " carbalkoxy " is meant the carbalkoxy that contains 2-7 carbon atom, and its specific examples comprises methoxycarbonyl, ethoxycarbonyl etc.Term " saturated heterocyclyl " is meant 5 yuan or 6 yuan of saturated heterocyclyls that comprise 1-2 the heteroatomic optional replacement that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, and its specific examples comprises the optional pyrrolidyl that replaces, piperidyl, morpholinyl, piperazinyl etc.
In the substituting group of the optional amino that replaces, the preferred optional acyl group that replaces, carbalkoxy and the optional alkyl that replaces, more preferably acyl group, carbalkoxy, alkyl, aminoalkyl group, alkoxycarbonyl amido alkyl and acylaminoalkyl.
The specific examples of " the optional amino that replaces " comprises amino, methylamino-, dimethylamino, N-ethanoyl-N-methylamino-, N-formyl radical-N-methylamino-, N-tertbutyloxycarbonyl-N-methylamino-, N-(3-(t-butoxycarbonyl amino) propyl group)-N-methylamino-, N-(3-aminopropyl)-N-methylamino-, N-(3-(kharophen) propyl group)-N-methylamino-, N-kharophen, methoxycarbonyl methylamino-, cyano group methylamino-, methoxycarbonyl amino etc.
(e) term " the optional saturated heterocyclyl that replaces " is meant; for example; comprise 1-4; preferred 1-2 heteroatomic 4 yuan of-7 yuan of saturated heterocyclyls that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom; this heterocyclic radical can have for example substituting group of carbalkoxy, acyl group, alkyl, oxo base etc., and can form condensed ring.Specific examples comprises: pyrrolidyl; 2-oxo-pyrrolidine base; imidazolidyl; pyrazolidyl; 2-oxo-oxazolidinyl; 4-oxo-oxazolidinyl; 4-oxo-Si Qing oxazinyl; 1; 1-dioxo-tetrahydrochysene isothiazolyl; piperidyl; piperidino-(1-position only); piperazinyl; 2-oxo piperazinyl; 4-methyl-2-oxo piperazinyl; 4-ethanoyl-2-oxo piperazinyl; morpholinyl; the morpholino base; 3-oxo morpholino base; thio-morpholinyl; thiomorpholine is for base; high piperazinyl; homopiperidinyl; high-piperidine sub-base etc.; preferred pyrrolidyl; 2-oxo-pyrrolidine base; piperidyl; piperidino-(1-position only); piperazinyl; the morpholino base; 3-oxo morpholino base; high-piperidine sub-base; high piperazinyl; 2-oxo-oxazolidinyl; 4-oxo-oxazolidinyl; 4-oxo-Si Qing oxazinyl; 1,1-dioxo-tetrahydrochysene isothiazolyl; 2-oxo piperazinyl; 4-methyl-2-oxo piperazinyl and 4-ethanoyl-2-oxo piperazinyl.
(3) example of Y " choosing the aryl that replaces wantonly " comprises that substituent aryl can be arranged, the saturated heterocyclyl of the carbonyl that the formamyl of for example optional alkyl that replaces of described substituting group, optional replacement, the saturated heterocyclyl that is optionally substituted replace, the optional amino that replaces, optional replacement etc.The example of " aryl " comprises the aryl radical that contains 6-14 carbon atom, be specially phenyl, naphthyl etc., and phenyl is preferred.
Herein, the substituting group on substituting group on the aryl and Y " the optional cycloalkyl that replaces " is identical.In above-mentioned all groups, the optional formamyl that replaces is preferred.
(4) term " optional replace saturated heterocyclyl " that is used for Y is meant, for example, comprises 1-4, preferred 1 or 25 yuan of-7 yuan of saturated heterocyclyl that are selected from the heteroatomic optional replacement of nitrogen-atoms, Sauerstoffatom and sulphur atom, and this heterocyclic radical can form condensed ring.Specific examples comprises imidazolidyl, pyrazolidyl, piperidyl, piperidino-(1-position only), piperazinyl, morpholinyl, morpholino base, thio-morpholinyl, thiomorpholine for base, high piperazinyl, homopiperidinyl, high-piperidine sub-base, pyrrolidyl etc., preferred pyrrolidyl, piperidyl, piperidino-(1-position only), piperazinyl, morpholino base, high-piperidine sub-base and high piperazinyl.The substituting group example of saturated heterocyclyl comprises (a) optional alkyl that replaces, (b) the optional saturated heterocyclyl that replaces, (c) the optional acyl group that replaces, (d) the optional unsaturated heterocycle base that replaces, (e) oxo base etc.
Herein, (a) example as substituent " alkyl " comprises the straight or branched alkyl that contains 1-6 carbon atom, is specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.This alkyl can have for example unsaturated heterocycle base (pyridyl etc.), optional by C 1-6The substituting group of the amino that alkyl replaces etc.
(b) example as substituent " the optional saturated heterocyclyl that replaces " is meant, for example, comprise 1 or 2 heteroatomic 5 yuan or 6 yuan of saturated heterocyclyl that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical can have for example substituting group of oxo base, and its specific examples is piperidyl, pyrrolidyl, 2-oxo-pyrrolidine base etc.Saturated heterocyclyl can be with C 1-6Alkyl, C 1-6Acyl groups etc. are as substituting group.
(c) example as substituent " acyl group " comprises alkyloyl, alkyl thiocarbonyl and alkyl sulphonyl.Term " alkyloyl " is meant, for example, contains the straight or branched alkyloyl of 1-6 carbon atom, is specially formyl radical, ethanoyl, propionyl, butyryl radicals etc.Term " alkyl thiocarbonyl " is meant, for example, contains the straight or branched alkyl thiocarbonyl of 2-6 carbon atom, is specially ethanethioyl, sulfo-propionyl etc.Term " alkyl sulphonyl " is meant, for example, contains the straight or branched alkyl sulphonyl of 1-6 carbon atom, is specially methylsulfonyl, ethylsulfonyl etc.Replacements such as the amino that this acyl group can be optionally substituted, pyridyl.
(d) example as substituent " the optional unsaturated heterocycle base that replaces " comprises, for example, comprise 1 or 2 heteroatomic 5 yuan or 6 membered unsaturated heterocycle base that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, be specially pyridyl, pyrimidyl, thiazolyl, oxazolinyl etc.
The example of " saturated heterocyclyl of replacement " comprises 3-oxo morpholino base, 2-oxo-pyrrolidine base, 1-sec.-propyl piperidyl, 1-formyl-dimethylamino piperidyl etc.
(5) example of Y " the optional unsaturated heterocycle base that replaces " is meant, for example, comprises 1-4, preferred 1 or 25 yuan-7 membered unsaturated heterocycle base that are selected from the heteroatomic optional replacement of nitrogen-atoms, Sauerstoffatom and sulphur atom, and this heterocyclic radical can form condensed ring.Specific examples comprises pyridyl, pyrimidyl, pyrazinyl, furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl etc.Preferred embodiment comprises pyridyl, pyrimidyl, pyrazinyl, thienyl, oxazolyl and thiazolyl.This unsaturated heterocycle base for example can have (a) optional amino that replaces, (b) the optional aminoalkyl group that replaces, (c) the optional saturated heterocyclyl that replaces, (d) substituting group of the optional formamyl that replaces etc.
(a) example as substituent " the optional amino that replaces " comprises the C that is replaced by amino 1-6Alkyl, this amino can be by C 1-6Alkyl replaces.
(b) comprise as the example of substituent " aminoalkyl group " and comprise C 1-6The aminoalkyl group of alkyl, this group can have for example C 1-6Alkyl, unsaturated heterocycle base (oxazolidinyl etc.) etc. substituting group.
(c) comprise as the example of substituent " optional replace saturated heterocyclyl " and comprise 1 or 2 heteroatomic 5 yuan of-7 yuan of saturated heterocyclyl that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom that specific examples comprises high piperazinyl etc.
(d) defined identical in the substituting group as the example of substituent " optional replace formamyl " and Y " cycloalkyl ".
The example of A " alkylidene group " comprises the straight or branched alkylidene group that contains 1-6 carbon atom, is specially methylene radical, ethylidene, trimethylene, tetramethylene, pentamethylene, hexamethylene etc.Wherein, preferably contain the alkylidene group of 1-5 carbon atom, preferred especially methylene radical and tetramethylene.Alkylidene group can be replaced by the oxo base, and its specific examples comprises propionyl, butyryl radicals, pentanoyl etc.
The example of A " alkene support base (alkenylene) " comprises the straight or branched alkene support base that contains 2-6 carbon atom, is specially vinylene, propenylene, 1,1,5-inferior pentenyl etc.The alkene support base that wherein contains 2-5 carbon atom is preferred.
The example of A " alkenylene (alkenylidene) " comprises the alkenylene that contains 2-6 carbon atom, is specially 1,1-vinylidene, 1,1-propenylidene, 1,1-crotonylidene, 1,1-inferior pentenyl etc.
R 1A, R 1BThe example of " halogen " comprise fluorine, chlorine, bromine, iodine etc.
R 1A, R 1BThe example of " alkyl " comprise contain 1-6 carbon atom, preferably contain the straight or branched alkyl of 1-4 carbon atom, be specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.Wherein, special preferable methyl.
R 1A, R 1BThe example of " haloalkyl " comprise by halogen replace contain 1-6 carbon atom, preferably contain the straight or branched alkyl of 1-4 carbon atom, be specially chloromethyl, dichloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl etc.
R 1A, R 1BThe example of " alkoxyl group " comprise contain 1-6 carbon atom, preferably contain the straight or branched alkoxyl group of 1-4 carbon atom, be specially methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy, hexyloxy etc.Wherein, preferred especially methoxyl group.
R 1A, R 1BThe substituent example of " optional replace amino " comprise contain 1-6 carbon atom, preferably contain the straight or branched alkyl of 1-4 carbon atom, be specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.Wherein, special preferable methyl.
R 1A, R 1BPreferred substituents be halogen and alkyl, preferred especially chlorine and methyl.
R 1CThe example and the R of " alkyl " and " halogen " 1A, R 1B" alkyl " defined identical with " halogen ".R 1CPreferred substituents be hydrogen.
R 2A, R 2BThe example of " halogen " comprise fluorine, chlorine, bromine, iodine etc., preferred fluorine, chlorine and bromine.
R 2A, R 2BThe example of " optional replace alkyl " comprise contain 1-6 carbon atom, preferably contain the straight or branched alkyl of 1-4 carbon atom, be specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc., special preferable methyl and ethyl.This alkyl can have for example can be by C 1-6Amino, hydroxyl, C that alkyl replaces 1-6Alkoxyl group, carboxyl, C 2-7The substituting group of carbalkoxy, the optional formamyl that replaces etc.The specific examples of the alkyl that replaces comprise aminomethyl, the methyl aminomethyl, dimethylaminomethyl, methylol, 2-hydroxyethyl, methoxyl methyl, carboxymethyl, methoxycarbonyl methyl, formyl-dimethylamino methyl etc., preferred especially methylol.
R 2A, R 2BThe example of " optional replace alkoxyl group " comprise contain 1-6 carbon atom, preferably contain the straight or branched alkoxyl group of 1-4 carbon atom, be specially methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy, hexyloxy etc.Wherein, preferred especially methoxyl group, oxyethyl group and isopropoxy.This alkoxyl group can have for example can be by C 1-6Amino, hydroxyl, C that alkyl replaces 1-6The substituting group of alkoxyl group etc.The specific examples of the alkoxyl group that replaces comprises amino ethoxy, dimethylamino ethoxy, hydroxyl-oxethyl, methoxyethoxy etc., preferred methoxyethoxy.
R 2A, R 2BThe substituent example of " optional replace amino " comprise C 1-6Alkyl, C 1-6Acyl group (for example alkyloyl, alkyl thiocarbonyl, alkyl sulphonyl), C 2-7Carbalkoxy etc.; be specially amino, methylamino-, dimethylamino, ethylamino, formamido group, kharophen, N-ethanoyl-N-methylamino-, N-methanesulfonamido, N-methyl-N-methanesulfonamido, methoxycarbonyl amino, t-butoxycarbonyl amino etc., preferred especially amino, dimethylamino, kharophen, methanesulfonamido and t-butoxycarbonyl amino.
R 2A, R 2BThe example of " optional replace carbalkoxy " comprise the straight or branched carbalkoxy that contains 2-7 carbon atom, be specially methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, butoxy carbonyl etc.This carbalkoxy can have for example hydroxyl, C 1-6The substituting group of alkoxyl group, the optional amino that replaces etc.
R 2A, R 2BThe substituent example of " optional replace formamyl " comprise the alkyl etc. of the optional replacement that contains 1-6 carbon atom.Alkyl can be by amino or C 1-6Alkoxyl group replaces, and wherein amino can be by C 1-6Alkyl or C 1-6Acyl group one replaces or two replacements.
The specific examples of formamyl comprises formamyl, N-methylamino formyl radical, N; N-formyl-dimethylamino, N-(2-methoxyethyl)-formamyl, N-methyl-N-methoxyethyl formamyl, N-(N; the N-dimethyl aminoethyl) formamyl, N-(N, N-dimethyl aminoethyl)-N-methylamino formyl radical etc.Wherein, preferred N, N-formyl-dimethylamino, N-methyl-N-methoxyethyl formamyl and N-(N, N-dimethyl aminoethyl)-N-methylamino formyl radical.
Be used for R 2A, R 2BTerm " carbonyl that the saturated heterocyclyl that is optionally substituted replaces " be meant that for example, what be optionally substituted contains 1-4, preferred 1 or 2 carbonyl that heteroatomic 5 yuan of-7 yuan of saturated heterocyclyls that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom replace.Its specific examples comprises imidazolidyl carbonyl, pyrazolidyl carbonyl, piperidino carbonyl, piperidino-(1-position only) carbonyl, piperazinyl carbonyl, morpholinyl carbonyl, morpholino carbonyl, thio-morpholinyl carbonyl, thiomorpholine for carbonyl, high piperazinyl carbonyl, homopiperidinyl carbonyl, high-piperidine sub-base carbonyl, pyrrolidyl carbonyl etc., preferred pyrrolidyl carbonyl, piperidino carbonyl, piperidino-(1-position only) carbonyl, piperazinyl carbonyl, morpholino carbonyl, high-piperidine sub-base carbonyl, high piperazinyl carbonyl etc.This saturated heterocyclyl can be by replacements such as oxo bases.
Be used for R 2A, R 2BTerm " optional replace saturated heterocyclyl " be meant that for example, comprise 1-4, preferred 1 or 2 heteroatomic 5 yuan of-7 yuan of saturated heterocyclyl that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical can have substituting group and can form condensed ring.Its specific examples comprises imidazolidyl, pyrazolidyl, piperidyl, piperidino-(1-position only), piperazinyl, morpholinyl, morpholino base, thio-morpholinyl, thiomorpholine for base, high piperazinyl, homopiperidinyl, high-piperidine sub-base, pyrrolidyl etc., preferred pyrrolidyl, piperidyl, piperidino-(1-position only), piperazinyl, morpholino base, high-piperidine sub-base and high piperazinyl.The substituent example of this saturated heterocyclyl comprises the optional alkyl that replaces, the optional saturated heterocyclyl that replaces, the optional acyl group that replaces, the optional unsaturated heterocycle base that replaces, oxo base etc., and " the optional saturated heterocyclyl that replaces " of these substituting groups and Y is defined identical.
R 2A, R 2BThe example of " acyl group " comprise the aryl radical that contains 6-14 carbon atom, be specially phenyl, naphthyl etc.
Be used for R 2A, R 2BTerm " optional replace unsaturated heterocycle base " be meant, for example, comprise 1-4, preferred 1 or 2 heteroatomic 5 yuan-7 membered unsaturated heterocycle base that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical can have substituting group, is specially pyridyl, pyrimidyl, pyrazinyl, furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl etc.The unsaturated heterocycle base can have substituting group, and for example optional two replace or monobasic amino (substituting group: C 1-4Alkyl, C 1-4Alkyloyl etc.), the optional alkyl (substituting group: that replaces by C 1-4Alkyl one replaces or dibasic amino C 1-4Alkyloyl etc.) etc.
R 2A, R 2BSubstituent preferred embodiment comprise the carbonyl that hydrogen, halogen, the optional alkyl that replaces, the optional alkoxyl group that replaces, the optional amino that replaces, cyano group, carboxyl, carbalkoxy, the optional formamyl that replaces or the saturated heterocyclyl that is optionally substituted replace.Wherein, hydrogen, fluorine, chlorine, bromine, methyl, methylol, methoxyl group, isopropoxy, amino, dimethylamino, methanesulfonamido, kharophen, t-butoxycarbonyl amino, cyano group, carboxyl, methoxycarbonyl, ethoxycarbonyl, formyl-dimethylamino, N-methyl-N-methoxyethyl-formamyl, morpholino carbonyl and pyrrolidyl carbonyl are preferred.
The example of " ring X " comprises following group:
With
Figure A20048000194100422
Wherein (a)-(f), (k) and (l) be preferred, (a) and (b) and (k) be especially preferred.Be preferably as follows group especially.
Be used for R 3Term " alkyl " be meant, for example, contain 1-6 carbon atom, preferably contain the straight or branched alkyl of 1-4 carbon atom, be specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.For R 3, hydrogen is particularly preferred.
Be used for R 4Term " alkyl " be meant, for example, contain 1-6, preferably contain the straight or branched alkyl of 1-4 carbon atom, be specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.For R 4, hydrogen is particularly preferred.
In this specification sheets, " saturated heterocyclyl " preferably comprises 5 yuan of-7 yuan of saturated heterocyclyls of the optional replacement of at least one nitrogen-atoms, the saturated heterocyclyl of nitrogen atom in the special preferably ring.
Ring:
Be preferably:
Figure A20048000194100425
Or
In the compound of the present invention, above-mentioned (1)-(110) compound is preferred.
The pharmacy acceptable salt of compound (I) comprises the salt that forms with mineral acid, and mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid etc. for example; With the salt that organic acid forms, organic acid is formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid etc. for example; With the salt that acidic amino acid forms, acidic amino acid is aspartic acid, L-glutamic acid etc. for example; With the salt that metal forms, metal is sodium, potassium, lithium, magnesium, calcium, aluminium etc. for example; With the salt that amine forms, amine is ammonia, methylamine, ethamine, thanomin etc. for example; The perhaps salt that forms with basic aminoacids, basic aminoacids is Methionin, ornithine etc. for example.
Compound of the present invention (I) can be the quaternary salt form, and such quaternary salt drops within compound of the present invention (I) scope.
Compound of the present invention (I) also comprises molecule inner salt, hydrate, solvate etc.In addition, when compound (I) when containing unsymmetrical carbon, this compound can exist with the optical isomer form, and the present invention comprises a kind of or mixture of these isomer.And, when compound (I) contains two keys or two or more substituent ring alkylidene groups are arranged on ring, its existence form can be cis, trans or meso-form, and when compound (I) contained unsaturated link(age) such as carbonyl, it can exist with tautomeric forms.Compound of the present invention (I) comprises a kind of or mixture of these isomer.
In addition, compound of the present invention (I) comprises the prodrug of above-claimed cpd.The example of prodrug comprises with the functional group of conventional protecting group to compound (I), for example amino or carboxyl protected and the prodrug for preparing.
Implement best mode of the present invention
Compound of the present invention can be prepared as follows.
Method 1: can prepare compound of the present invention (I) with following mode.
Wherein each symbol definition as above.
Compound (I) can prepare by making compound (II) and compound (III) carry out condensation reaction.
The condensation of compound (II) and compound (III) can be carried out in the following way: use condensing agent that these compounds are carried out conventional condensation reaction; or compound (III) changed into reactive derivative (acyl halide, mixed anhydride, active ester etc.), and and compound (II) reaction.
(1) compound (II) and compound (III) are being carried out under the situation of conventional condensation reaction, reaction can be carried out in suitable solvent.The condensing agent that is applicable to this reaction comprises N, N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) or its hydrochloride, carbonyl dimidazoles (CDI), diphenylphosphine acyl group-trinitride (DPPA), diethylcyanophosphonise (DEPC) etc.Wherein, DCC, EDC or its hydrochloride are preferred.
The present invention carries out under 0 ℃-100 ℃ temperature usually; But, if desired, can suitably select higher or lower temperature.Reaction times of the present invention was generally 30 minutes-24 hours; But, if desired, can suitably select the longer or shorter reaction times.
(2) under the situation of the reactive derivative that uses compound (III); mode with routine changes into reactive derivative with compound (III); for example; use halogenating agent (thionyl chloride; thionyl bromide; oxalyl chloride etc.) convert it into acyl halide; use chloro-formic ester (methyl-chloroformate; Vinyl chloroformate; isobutyl chlorocarbonate etc.) or chloride of acid (2; 4; 6-trichloro-benzoyl chloride etc.) convert it into mixed acid anhydride; use 1-maloyl imines; I-hydroxybenzotriazole or p-NP etc., perhaps low-carbon-ester (methyl esters; ethyl ester etc.) convert it into active ester.Then resulting reactive derivative and compound (II) are carried out condensation reaction, condensation reaction is carried out in suitable solvent or without solvent, when needs, is carried out in the presence of acid scavenger.
This condensation reaction preferably changes into compound (III) method of acyl halide.
When reaction relates to conversion to acyl halide, can come accelerated reaction as catalyzer by adding dimethyl formamide etc.
In addition, in above-mentioned condensation reaction, can wait by the adding 4-dimethylaminopyridine to promote or accelerated reaction.
The acid scavenger that uses when needing comprises for example inorganic or organic bases.The example of mineral alkali comprises alkaline carbonate (yellow soda ash, salt of wormwood, cesium carbonate etc.), alkali metal hydrocarbonate (sodium bicarbonate, saleratus etc.) and alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.).The example of organic bases comprises linear three low-grade alkylamines (triethylamine, Tributylamine, diisopropylethylamine etc.), ring-type tertiary amine (1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene etc.), aromatic series tertiary amine (N, accelerine, N, N-Diethyl Aniline etc.), pyridine, lutidine, collidine etc.Wherein, this reacts preferred triethylamine, diisopropylethylamine and pyridine.If use acid scavenger in reaction, this acid scavenger can serve as solvent.
This reaction is carried out under-20 ℃-solvent refluxing temperature usually; But, if desired, can suitably select lower temperature.Reaction times of the present invention was generally 30 minutes-24 hours; But, if desired, can suitably select the longer or shorter reaction times.
In above-mentioned condensation reaction, use under the situation of solvent, can use not any inert solvent of disturbance reponse, for example, halogenated solvent (chloroform, methylene dichloride, ethylene dichloride etc.), aromatic hydrocarbon (benzene,toluene,xylene etc.), ether (ether, Di Iso Propyl Ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.), ester (ethyl acetate etc.), acid amides (N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1,3-dimethyl-2-imidazolidone etc.), nitrile (acetonitrile etc.), methyl-sulphoxide, pyridine, 2,6-lutidine, water etc.Can also use the mixed solvent that comprises two kinds or more of these solvents.In the solvent, preferred methylene dichloride, chloroform, toluene, dimethylbenzene, tetrahydrofuran (THF), diox, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1,3-dimethyl-2-imidazolidone and pyridine, preferred especially methylene dichloride, chloroform, N, dinethylformamide, pyridine and mixed solvent thereof.
Method 2: in the compound (I), Y is by-N (G) R 5,-NHR 5With-N (R 5) CH 2R 6The compound of the cycloalkyl that replaces promptly is respectively compound (I-a), (I-b) and (I-c), can prepare with following mode.
Figure A20048000194100451
Y wherein 1Be the ring alkylidene group, R 5Be hydrogen, alkyl, acyl group, carbalkoxy or unsaturated heterocycle base, R 6Be optional alkyl or the unsaturated heterocycle base that replaces, G is an amino protecting group, for example tertbutyloxycarbonyl, carbobenzoxy-(Cbz) etc., and other symbols are with defined above identical.
Compound (I-b) can obtain compound (I-a) by compound (II) and compound (III-a) condensation, and removes amino protecting group and prepare.Subsequently, can use general formula: R 6The aldehyde of CHO carries out standard reductive alkylation and prepares compound (I-c) compound (I-b).
Condensation between compound (II) and the compound (III-a) can be carried out being similar under the method 1 described condition.
Can adopt normally used method in the synthetic organic chemistry field to carry out the protective reaction of compound (I-a).For example, when the G of compound (I-a) is tertbutyloxycarbonyl, can be at suitable solvent (diox, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, chloroform, methyl alcohol, ethanol etc.) in handle this compound with acid (for example hydrochloric acid, trifluoroacetic acid, methylsulfonic acid etc.), obtain compound (I-b).
Can be in the presence of reductive agent, in suitable solvent, with compound (I-b) and aldehyde (R 6CHO) the standard reductive alkylation reaction of compound (I-b) is carried out in reaction.
In standard reductive alkylation reaction, can use any reductive agent that does not influence amido linkage etc., the example comprises metallic reducing agent, for example sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride etc.
In the standard reductive alkylation reaction, can use not any inert solvent of disturbance reponse, for example, halogenated solvent (chloroform, methylene dichloride, ethylene dichloride etc.), ether (ether, Di Iso Propyl Ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.), acid amides (N, dinethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidone etc.), nitrile (acetonitrile etc.), aromatic hydrocarbon (benzene,toluene,xylene etc.), alcohols (methyl alcohol, ethanol, propyl alcohol etc.), water etc.When needs, can also use the mixed solvent that comprises two kinds or more of these solvents.Wherein, methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, methyl alcohol, ethanol, propyl alcohol etc. are preferred.
Standard reductive alkylation reaction is carried out under-10 ℃-solvent refluxing temperature usually, and preferable reaction temperature is the temperature-room temperature under ice-cooled.Reaction times was generally 30 minutes-24 hours; But, if desired, can suitably select the longer or shorter reaction times.
Can also replace above-mentioned reductive agent with metal catalyst (palladium-carbon, platinum-carbon, platinum oxide, Raney nickel etc.), carry out catalytic hydrogenation with hydrogen and carry out this reaction.
Among the present invention, can use not any inert solvent of disturbance reponse, for example, ether (ether, Di Iso Propyl Ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.), acid amides (N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1,3-dimethyl-2-imidazolidone etc.), ester class (ethyl acetate etc.), aromatic hydrocarbon (benzene,toluene,xylene etc.), alcohols (methyl alcohol, ethanol, propyl alcohol etc.), water etc.If suitable, can also use to comprise mixed solvents two kinds or more of in these solvents.Wherein, tetrahydrofuran (THF), N, dinethylformamide, methyl alcohol and ethanol are preferred.
This reaction is carried out under-10 ℃-solvent refluxing temperature usually, and preferable reaction temperature is the temperature-room temperature under ice-cooled.Reaction times was generally 30 minutes-24 hours; But, if desired, can suitably select the longer or shorter reaction times.
In addition, in order to promote the standard reductive alkylation reaction, can also add such as the organic acid of acetate or the mineral acid of all example hydrochloric acids.
Method 3: compound of the present invention (I) can also prepare in the following way.
Figure A20048000194100471
Wherein R is hydrogen, C 1-4Alkyl or carboxyl-protecting group, other symbol definitions as above.
Can make compound (IV) and compound (V) that condensation reaction takes place and prepare compound (I).
Can carry out the condensation reaction of compound (IV) and compound (V) in the following way: without solvent, heat these compounds, perhaps in the presence of three low alkyl group aluminium (trimethyl aluminium), diethyl dihydro sodium aluminate etc., in suitable solvent, compound (V) is changed into corresponding aluminium amide compound, and and compound (IV) reaction.
In the reaction, can use not any inert solvent of disturbance reponse, for example, halogenated solvent (chloroform, methylene dichloride, ethylene dichloride etc.), aromatic hydrocarbon (benzene,toluene,xylene etc.), ether (ether, Di Iso Propyl Ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.), acid amides (N, dinethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidone etc.), hydro carbons (hexane etc.), methyl-sulphoxide, pyridine, 2, the 6-lutidine, water etc., and comprise mixed solvents two kinds or more of in these solvents.Wherein, methylene dichloride, chloroform, toluene, dimethylbenzene and hexane are particularly preferred.
This reaction can carried out in a wide temperature range that is cooled to heat, and for example, from the boiling point of-10 ℃-solvent, special preferable reaction temperature is the temperature-60 ℃ under ice-cooled.Reaction times becomes according to solvent for use; But, be generally 1-24 hour, be preferably 2-8 hour.
Method 4:
In the compound (II), following a kind of compound, wherein R 4Be hydrogen, and ring:
Figure A20048000194100481
Be
Figure A20048000194100482
Perhaps
Wherein symbol definition as above, that is, and the compound of general formula (II-a):
Wherein encircle:
Figure A20048000194100485
Be
Perhaps
Figure A20048000194100487
Other symbol definitions as above can prepare with following mode.
Wherein Hal is a halogen, for example chlorine, bromine etc., and other symbol definitions are as above.
(1) the O-alkylated reaction of compound (VI-a) if necessary, can carry out in suitable solvent in the presence of alkali.
The alkali that can be used for the O-alkylated reaction comprises, for example, and inorganic and organic bases.The example of mineral alkali comprises alkaline carbonate (yellow soda ash, salt of wormwood, cesium carbonate etc.), alkali metal hydrocarbonate (sodium bicarbonate, saleratus etc.), alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.) etc.In the O-alkylated reaction, halogenide (sodium iodide, lithium iodide, potassiumiodide, lithiumbromide etc.), preferred iodide (sodium iodide, lithium iodide, potassiumiodide etc.) and alkali use together.
The example of organic bases comprises linear three low-grade alkylamines (triethylamine, Tributylamine, diisopropylethylamine etc.), ring-type tertiary amine (1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene etc.), aromatic series tertiary amine (N, accelerine, N, N-Diethyl Aniline, 4-dimethylaminopyridine etc.), pyridine, lutidine, collidine etc.In addition, can also use alkali such as alkali metal alkoxide (sodium methylate, butanols potassium etc.).For this reaction, alkaline carbonate is particularly preferred.In this reaction, these alkali can also serve as solvent.
In the O-alkylated reaction, can use not any inert solvent of disturbance reponse, for example, ketone (acetone, methyl ethyl ketone etc.), aromatic hydrocarbon (benzene,toluene,xylene etc.), ether (ether, Di Iso Propyl Ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.), acid amides (N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1,3-dimethyl-2-imidazolidone etc.), nitrile (acetonitrile etc.), methyl-sulphoxide, pyridine, 2,6-lutidine etc.Can also use and comprise mixed solvents two kinds or more of in these solvents.Wherein, ketone and acid amides are preferred.
This reaction is usually carried out under the temperature of the temperature-solvent refluxing temperature under ice-cooled.Reaction times was generally 30 minutes-24 hours; But, if desired, can suitably select the longer or shorter reaction times.
(2) cyclization of compound (VIII-a), if necessary, can be in suitable solvent, by carrying out with alkaline purification.
Can use when carrying out cyclization with the described bases of above-mentioned O-alkylated reaction like alkali, preferably use the alkali of alkaline carbonate, potassium tert.-butoxide or ring-type tertiary amine.
In cyclization, use under the situation of solvent, can use not any inert solvent of disturbance reponse, for example, ketone (acetone, methyl ethyl ketone etc.), aromatic hydrocarbon (benzene,toluene,xylene etc.), ethers (ether, Di Iso Propyl Ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.), acid amides (N, dinethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidone etc.), nitrile (acetonitrile etc.), alcohols (methyl alcohol, ethanol, propyl alcohol, 2-butanols, the trimethyl carbinol etc.), methyl-sulphoxide, pyridine, 2,6-lutidine etc.Can also use and comprise mixed solvents two kinds or more of in these solvents.Wherein, ketone, acid amides and alcohols are preferred, preferred especially N,N-dimethylacetamide, 1, the 3-dimethyl-2-imidazolidone and trimethyl carbinol.
This reaction is usually carried out under the temperature of the temperature-solvent refluxing temperature under ice-cooled.The reaction times of cyclisation was generally 30 minutes-24 hours; But, if desired, can suitably select the longer or shorter reaction times.
Method 5:
In the compound (II), following compound, wherein R 4Be hydrogen, and ring:
Be
Figure A20048000194100502
Perhaps
Figure A20048000194100503
Wherein symbol definition as above, that is, and the compound of general formula (II-b):
Wherein encircle:
Be
Figure A20048000194100513
Perhaps
Other symbol definitions as above can prepare with following mode.
Wherein symbol definition as above.
(1) reaction between compound (VI-b) and the compound (VII-b) if necessary, can be carried out in suitable solvent in the presence of alkali.The example that can be used for the alkali of this reaction comprises alkaline carbonate (yellow soda ash, salt of wormwood, cesium carbonate etc.), alkalimetal hydride (sodium hydride etc.) and alkali metal alkoxide (sodium methylate, potassium tert.-butoxide etc.).Wherein preferred especially sodium hydride.Solvent comprises acid amides (N, dinethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidone etc.) and ethers (ether, Di Iso Propyl Ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.).Wherein, N, dinethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidone etc. is preferred.
(2) cyclization of compound (VIII-b) can carry out under the condition that is similar to the used condition of cyclization described in the method 3.
Method 6:
Compound (IV) can prepare with following mode.
Wherein symbol definition as above.
Compound (IV) can prepare by the condensation reaction of compound (IX) and compound (III).Condensation reaction can be carried out being similar under the condition described in the method 1.
Method 7:
In the compound (IX), R 4The compound that is hydrogen can prepare with following mode.
Wherein symbol definition as above.
The preparation method of compound (IX-a) can be: in the presence of alkali, make compound (VI-a) and compound (VII-c) carry out the O-alkylation, the more resulting compound VIII-c of cyclisation.The reaction separately of O-alkylation and cyclization can be carried out being similar under the condition described in the method 4.
Method 8:
Compound (VII-a) can prepare with following mode.
Wherein symbol definition as above.
Compound (VII-a) can prepare by following approach: use condensing agent that compound (X) and compound (XI) are carried out conventional condensation reaction; perhaps compound (X) is changed into reactive derivative (acyl halide, mixed acid anhydride, active ester etc.), and and compound (XI) reaction.
This reaction can be carried out being similar under the method 1 described condition.Especially preferably use the method for the reactive derivative (acyl halide) of compound (X).
Method 9:
Compound (VII-b) can prepare with following mode.
Wherein Ac is an ethanoyl, and other symbol definitions as above.
Compound (VII-b) can prepare by following approach: according to the ordinary method that halogenide is changed into hydroxyl, in suitable solvent with compound (VII-a) and acetic acid sodium reaction, and with (XII) solvolysis of resulting compound or hydrolysis.
In this reaction, can use not any inert solvent of disturbance reponse, preferred amide (N, dinethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidone etc.).
This reaction is carried out under 0 ℃-100 ℃ temperature usually; But, if desired, can suitably select higher or lower temperature.Reaction times was generally 30 minutes-24 hours; But, if desired, can suitably select the longer or shorter reaction times.
Compound (VII-b) can be by the preparation of following approach: in the solvent of for example alcohol (methyl alcohol, ethanol etc.), water etc., with mineral alkali etc., perhaps in inert solvent, with alkali metal alkoxide or mineral alkali, (XII) handles to compound.The mineral alkali that can be used for this reaction comprises alkaline carbonate (yellow soda ash, salt of wormwood etc.), alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), special preferred alkali metal carbonate.
The alkali metal alkoxide that can be used for this reaction comprises sodium methylate, potassium tert.-butoxide etc.
In this reaction, can use not any inert solvent of disturbance reponse, for example, alcohols (methyl alcohol, ethanol, propyl alcohol, 2-butanols etc.), water, acid amides (N, dinethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidone etc.), ethers (ether, Di Iso Propyl Ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.) etc.Can also use and comprise mixed solvents two kinds or more of in these solvents.Wherein, the first alcohol and water is preferred.
Method 10:
In the compound (III-a), R 5The compound that is hydrogen can prepare with following mode.
Figure A20048000194100541
Wherein Ra is an alkyl, methyl for example, and other symbol definitions are as above.
Compound (XIII-b) can prepare by following approach: by the Curtius rearrangement reaction compound (XII) is changed into compound (XIII), wherein in the presence of alkali, in suitable solvent, handle compound (XII) with trinitride, if necessary, can add activator, and handle with alcohol.Compound (XIII-a) can prepare by hydrolysis compound (XIII-b).
The example that can be used for the alkali of Curtius rearrangement reaction comprises triethylamine, diisopropylethylamine etc.
When needs, the activator that can be used for the Curtius rearrangement reaction comprises methyl-chloroformate, Vinyl chloroformate, isopropyl chlorocarbonate, isobutyl chlorocarbonate, phenyl chloroformate etc.
The trinitride that can be used for the Curtius rearrangement reaction comprises sodiumazide, diphenyl phosphoryl azide etc.
The example that can be used for the solvent of Curtius rearrangement reaction comprises toluene, dimethylbenzene, benzene, tetrahydrofuran (THF), diox, ethylene glycol dimethyl ether, dimethyl formamide, chloroform, ethylene dichloride, ethyl acetate, acetonitrile, the trimethyl carbinol etc.When using the trimethyl carbinol as solvent, following alcohol is handled and is not necessarily required, and only just can obtain compound (XIII-b) by above-mentioned processing.
The Curtius rearrangement reaction is carried out under-20 ℃-150 ℃ temperature usually; But, if desired, can select higher or lower temperature.
The reaction times of Curtius rearrangement reaction was generally 30 minutes-10 hours; But, if desired, can select the longer or shorter reaction times.
The example of the alcohol that can use when preparation compound (XIII-b) comprises the straight or branched C that can contain phenyl 1-4Alcohol is specially methyl alcohol, ethanol, the trimethyl carbinol, benzylalcohol etc.
The reaction that obtains compound (XIII-b) is carried out under the temperature of-20 ℃-solvent refluxing temperature usually; But, if desired, can select higher or lower temperature.
The reaction times that obtains compound (XIII-b) was generally 30 minutes-24 hours; But, if desired, can suitably select the longer or shorter reaction times.
Can the compound (XIII-b) that obtain be changed into compound (XIII-a) by compound (XXX-b) being carried out the normally used known hydrolysis reaction in synthetic organic chemistry field.
Method 11:
When compound of the present invention contains amino, can adopt the known method in synthetic organic chemistry field with its N-alkylation or N-acidylate.When compound of the present invention contains formamyl or amide group, can adopt the known method in synthetic organic chemistry field with its N-alkylation.When compound of the present invention contains carboxyl, can adopt the known method in synthetic organic chemistry field with its esterification or amidation.When compound of the present invention contains ester or acid amides, can adopt the known method in synthetic organic chemistry field to convert it into corresponding carboxylic acid, alkohol and amine by hydrolysis or reduction.
When compound of the present invention has halogen atom on aryl or unsaturated heterocycle base, can adopt the known method in Synthetic Organic Chemistry field, for example use the coupled reaction of palladium or nickel catalyzator, convert it into corresponding aryl, unsaturated heterocycle base, optional amino and the alkoxyl group that replaces.When above-mentioned coupled reaction is when carrying out, can convert it into corresponding carbalkoxy or the optional formamyl that replaces in carbon monoxide atmosphere.
The method that can adopt the synthetic organic chemistry field to know, for example recrystallization, column chromatography etc. separate the The compounds of this invention that obtains with the such preparation of purifying.
Compound of the present invention (I) or its pharmacy acceptable salt have fabulous restraining effect to activatory blooc coagulation factor X; therefore; (for example can be used for prevention and treatment Mammals; the people; monkey; rabbit; dog; cat; pig; horse; bull; mouse; rat; cavy etc.) the various obstacles that cause by thrombus and embolus in; these obstacles comprise; for example; stablize stenocardia; unstable angina; cerebral thrombosis; cerebral infarction; cerebral embolism; transient ischemic attack (TIA); ischemic cerebrovascular; the cerebral vasospasm after the subarachnoid hemorrhage for example; the ischemic heart disease that causes by Coronary thrombosis; congested chronic heart failure; myocardial infarction; acute myocardial infarction; the lung infraction; pulmonary infarction; pulmonary vascular disease; economic class syndromes; kidney disease (diabetic kidney disease; chronic glomerulonephritis; IgA nephropathy etc.); the thrombosis of atherosclerosis association (thrombogenesis with atherosclerosis); periphery artery occlusion; the peripheral vein obturation; the Burger disease; venous thrombosis; disseminated intravascular coagulation (DIC); thrombosis after replace in synthetic vascular prosthesis transplanting or prosthetic heart valve or joint; intermittent claudication; thrombosis after blood circulation is rebuild and inaccessible again, for example thrombosis after the logical again art (PTCR) and inaccessible again in percutaneous tranluminal coronary angioplasty (PTCA) or the percutaneous coronary chamber; systemic inflammatory reaction syndromes (SIRS); multiple organ dysfunction syndrome (MODS); thrombosis in the extracorporeal circulation; blood coagulation under blood drawing (blood drawing) situation; diabetic cycle penalty; transplant rejection; function improvement under Organoprotective and the transplanting situation etc.
The compounds of this invention is characterised in that: it demonstrates the fabulous restraining effect to activatory blooc coagulation factor X, and toxicity reduces, and only produces seldom visible side effect in existing anticoagulant (bleed etc.).
Compound of the present invention (I) or its pharmacy acceptable salt can be re-dubbed the compound (I) that comprises effective therapeutic dose and the pharmaceutical composition of its pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier comprises thinner, tackiness agent (for example syrup, gum arabic, gelatin, sorb (sugar) alcohol, tragacanth gum, polyvinylpyrrolidone), vehicle (for example, lactose, sucrose, W-Gum, potassiumphosphate, sorb (sugar) alcohol, glycine), lubricant (for example, Magnesium Stearate, talcum, polyoxyethylene glycol, silica), disintegrating agent (for example yam starch) and wetting agent (for example sodium lauryl sulphate) etc.
Compound of the present invention (I) or its pharmacy acceptable salt can oral or parenteral admins, and can use with suitable pharmaceutical preparation.Suitable peroral administration examples of formulations comprises solid preparation (tablet, granule, capsule, pulvis etc.), solution, suspensoid and emulsion.The preparation of suitable parenteral admin comprises suppository, injection or the continuous transfusion preparation or the inhalation that prepare with distilled water for injection, physiological saline or glucose solution etc.
The dosage of compound of the present invention (I) or its pharmacy acceptable salt can be according to route of administration and patient's age, body weight and state, the perhaps kind of disease or severity and change, be generally about 0.1-50mg/kg/ days, preferably about 0.1-30mg/kg/ days.
Embodiment
The present invention will be elaborated by embodiment and reference example, still not be to be understood that to be limited.
Embodiment 1:N-(5-chloropyridine-2-yl)-3-(trans-4-(2-oxo-tetramethyleneimine-1-yl) cyclohexyl] and carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide
Trans-4-(2-oxo-pyrrolidine-1-yl) hexahydrobenzoic acid (22.0g) that obtains in the reference example 2 is dissolved in the thionyl chloride (150ml), at room temperature stirred the mixture 6 hours.The concentrating under reduced pressure reaction soln is suspended in resistates in the chloroform (500ml).Under ice-cooled condition, in suspension, add 3-amino-N-(5-chloropyridine-2-yl) furo [3, the 2-b] pyridine-2-carboxamides (20.0g) that obtain in the reference example 24 with the aliquot form.To wherein dripping pyridine (56ml), reaction soln is warmed to room temperature, and stirred 15 hours.In ice-cooled condition downhill reaction solution, pour saturated sodium bicarbonate aqueous solution into, the mixture chloroform extraction.Organic layer is water and saturated brine washing successively, uses dried over sodium sulfate, and the evaporation under reduced pressure solvent.Resulting resistates NH-silica gel column chromatography (elutriant: ethyl acetate/methanol=10/1, follow by chloroform) purifying.Under thermal condition, resulting resistates is suspended in the ethyl acetate.Filter collecting precipitation thing and dry, obtain title compound (32.2g).APCI-MS M/Z：482/484[M+H] +。
Title compound is further handled in a usual manner with methylsulfonic acid, Phenylsulfonic acid, sulfuric acid and hydrochloric acid, obtained the corresponding salt of title compound.
Mesylate: APCI-MS M/Z:482/484[M+H] +
Two-mesylate: APCI-MS M/Z:482/484[M+H] +
Benzene sulfonate: APCI-MS M/Z:482/484[M+H] +
Two-benzene sulfonate: APCI-MS M/Z:482/484[M+H] +
Vitriol: APCI-MS M/Z:482/484[M+H] +
Hydrochloride: APCI-MS M/Z:482/484[M+H] +
Embodiment 2:N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide
Trans-4-(the 3-oxo morpholine-4-yl) hexahydrobenzoic acid (118mg) that obtains in the reference example 4 is dissolved in the thionyl chloride (3ml), at room temperature stirred the mixture 12 hours.The concentrating under reduced pressure reaction soln is dissolved in resistates in the chloroform (5ml).Under ice-cooled condition, in solution, add 3-amino-N-(5-chloropyridine-2-yl) furo [3, the 2-b] pyridine-2-carboxamides (100mg) that obtain in the reference example 24.To wherein adding pyridine (280 μ l), reaction soln is warmed to room temperature, and stirred 12 hours.In reaction soln, pour saturated sodium bicarbonate aqueous solution into, the mixture chloroform extraction.Organic layer is water and saturated brine washing successively, uses dried over sodium sulfate, and the evaporation under reduced pressure solvent.Resulting resistates NH-silica gel column chromatography (elutriant: ethyl acetate then is ethyl acetate/methanol=10/1) purifying.With resulting solid suspension in ethyl acetate-ether.Filter the collecting precipitation thing, obtain title compound (120mg).APCI-MS M/Z：498/500[M+H] +。
Embodiment 3-78
Employing and embodiment 2 similar modes are handled corresponding aminocompound and carboxylic acid cpd, obtain following compound.
Table 1
Figure A20048000194100601
Table 2
Table 3
Figure A20048000194100621
Table 4
Table 5
Figure A20048000194100641
Table 6
Table 7
Figure A20048000194100661
Table 8
Table 9
Figure A20048000194100681
Table 10
Figure A20048000194100691
Table 11
Table 12
Figure A20048000194100711
Table 13
Table 14
Table 15
Table 16
Table 17
Table 18
Table 19
Embodiment 79:2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylic acid
With the 2-{[(5-chloropyridine-2-yl that obtains among the embodiment 39) amino] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylate methyl ester (9.40g) is suspended in the tetrahydrofuran (THF) (135ml), under ice-cooled condition to wherein adding 1N aqueous sodium hydroxide solution (34ml).Mixture is warmed to room temperature, stirred 3 hours.In ice-cooled condition downhill reaction solution, pour 2N hydrochloric acid (17ml) into, and the concentrating under reduced pressure reaction soln.Resistates is suspended in the water, filters the collecting precipitation thing.Resulting solid water and ether washing obtain title compound (7.83g).
ESI-MS M/Z：540/542[M-H] -
Embodiment 80-84
Employing and embodiment 79 similar modes are handled corresponding precursor compound, obtain following compound.
Table 20
Figure A20048000194100801
Table 21
Embodiment 85:N-(5-chloropyridine-2-yl)-5-(morpholine-4-base carbonyl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194100812
With the 2-{[(5-chloropyridine-2-yl that obtains among the embodiment 79) amino] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylic acid (100mg) is dissolved in N, in the dinethylformamide (3ml), to wherein adding morpholine (32 μ l), I-hydroxybenzotriazole (50mg) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (71mg) successively, and at room temperature stirred this mixture 15 hours.With ethyl acetate-tetrahydrofuran (THF) diluting reaction solution, and with solution usefulness saturated sodium bicarbonate aqueous solution successively, water and saturated brine washing, dried over sodium sulfate.Evaporating solvent under the reduced pressure is suspended in resulting resistates in ethyl acetate-ether.The solid collected by filtration throw out obtains title compound (109mg).
APCI-MS M/Z：611/613[M+H] +。
Embodiment 86-93
Employing and embodiment 85 similar modes are handled corresponding precursor compound, obtain following compound.
Table 22
Table 23
Embodiment 94:[2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-yl] t-butyl carbamate
Figure A20048000194100851
With the 2-{[(5-chloropyridine-2-yl that obtains among the embodiment 79) amino] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylic acid (6.80g) is suspended in the trimethyl carbinol (300ml).At room temperature in suspension, add triethylamine (3.48ml) and diphenylphosphine acylazide thing (5.39ml), mixture was stirred 15 hours down at 100 ℃.The concentrating under reduced pressure reaction soln.Resistates dilutes with chloroform, water and saturated brine washing.The organic layer dried over sodium sulfate, the evaporation under reduced pressure solvent.Resulting resistates obtains title compound (5.64g) with silica gel column chromatography (elutriant: chloroform/methanol=100/1 is 20/1 subsequently) purifying.
APCI-MS M/Z：613/615[M+H] +。
Embodiment 95-99
Employing and embodiment 94 similar modes are handled corresponding precursor compound, obtain following compound.
Table 24
Figure A20048000194100861
Table 25
Embodiment 100:5-amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide hydrochloride
With [2-{[(5-chloropyridine-2-yl) amino] carbonyl that obtains among the embodiment 94 }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-yl] t-butyl carbamate (5.55g) is suspended in the methyl alcohol (20ml), under ice-cooled condition to wherein adding 4N hydrochloric acid-dioxane solutions (50ml).At room temperature stirred the mixture 8 hours.The concentrating under reduced pressure reaction soln is suspended in resulting resistates in the ether.Filter the collecting precipitation thing, obtain title compound (4.67g).
APCI-MS M/Z：513/515[M+H] +。
Embodiment 101:5-amino-N-(5-chloropyridine-2-yl)-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194100881
With (2-{[(5-chloropyridine-2-yl) amino that obtains among the embodiment 96] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-5-yl) t-butyl carbamate (280mg) is suspended in the diox (3ml).In suspension, add 4N hydrochloric acid-dioxane solutions (3ml).Reaction soln is warmed to room temperature, and, stirred subsequently 8 hours to wherein adding methyl alcohol (2ml).The concentrating under reduced pressure reaction soln is suspended in resulting resistates in the ether.Filter the collecting precipitation thing, obtain the hydrochloride (266mg) of title compound.Resulting hydrochloride is suspended in the chloroform, and adds saturated sodium bicarbonate aqueous solution.By the solid collected by filtration throw out, obtain title compound (88mg).
APCI-MS M/Z：483/485[M+H] +。
Embodiment 102-105
Employing and embodiment 100 or 101 similar modes are handled corresponding precursor compound, obtain following compound.
Table 26
Figure A20048000194100891
Embodiment 106:N-(5-chloropyridine-2-yl)-5-[(methylsulfonyl) amino]-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide
With 5-amino-N-(5-chloropyridine-2-the yl)-3-{[(that obtains among the embodiment 101 trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide (110mg) is dissolved in the pyridine (3ml), under ice-cooled condition to wherein adding methylsulfonyl chloride (46 μ l).At room temperature stirred the mixture 3 hours.In reaction soln, add saturated sodium bicarbonate aqueous solution, the mixture chloroform extraction.The organic layer dried over sodium sulfate, solvent evaporated under reduced pressure.Resulting resistates silica gel column chromatography (elutriant: chloroform, follow by chloroform/methanol=20/1) purifying.Resulting solid suspension in ether, is filtered collection and obtains title compound (76mg).
APCI-MS M/Z：591/593[M+H] +。
Embodiment 107-114
Employing and embodiment 106 similar modes are handled corresponding precursor compound, obtain following compound.
Table 27
Table 28
Embodiment 115:N-(5-chloropyridine-2-yl)-5-(methylol)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide
With the 2-{[(5-chloropyridine-2-yl that obtains among the embodiment 39) amino] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylate methyl ester (300mg) is suspended in the tetrahydrofuran (THF) (15ml), under ice-cooled condition,, at room temperature stirred the mixture 20 hours to wherein adding lithium borohydride (24mg).In ice-cooled condition downhill reaction solution, pour 10% hydrochloric acid into, mixture was at room temperature stirred 15 minutes.Reaction soln is alkalized with saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction then.Organic layer washs with saturated brine, dried over sodium sulfate, and solvent evaporated under reduced pressure.Resulting resistates NH-silica gel column chromatography (elutriant: ethyl acetate, follow by ethyl acetate/methanol=10/1) purifying.Resulting solid suspension in ether-normal hexane, is filtered collection and obtains title compound (80mg).
APCI-MS M/Z：528/530[M+H] +。
Embodiment 116 and 117
Employing and embodiment 115 similar modes are handled corresponding precursor compound, obtain following compound.
Table 29
Figure A20048000194100941
Embodiment 118:(is trans-4-{[(2-{[(5-chloropyridine-2-yl) and amino]-carbonyl } furo [3,2-b] pyridin-3-yl) amino] carbonyl } cyclohexyl)-the methyl carbamic acid tert-butyl ester
With the trans-4-[(tertbutyloxycarbonyl that obtains in the reference example 12) (methyl) amino] hexahydrobenzoic acid (1.30g) is dissolved in the chloroform (30ml), to wherein adding pyridine (2.80ml).Under ice-cooled condition, add thionyl chloride (0.38ml), afterwards mixture was at room temperature stirred 5 hours.Under ice-cooled condition, in resulting reaction soln, add 3-amino-N-(5-chloropyridine-2-yl) furo [3, the 2-b] pyridine-2-carboxamides (1.00g) and the pyridine (7.20g) that obtain in the reference example 24 successively.Reaction soln is warmed to room temperature, and stirred 3 hours.In reaction soln, pour saturated sodium bicarbonate aqueous solution into, the mixture chloroform extraction.Organic layer is water and saturated brine washing successively, dried over sodium sulfate.Solvent evaporated under reduced pressure, (elutriant: ethyl acetate) purifying obtains title compound (1.71g) to resistates with silica gel column chromatography.
APCI-MS M/Z：528/530[M+H] +。
Embodiment 119:N-(5-chloropyridine-2-yl)-3-({ [trans-4-(methylamino-)-cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide tri hydrochloride
Figure A20048000194100951
With (trans-4-{[(2-{[(5-chloropyridine-2-yl) amino that obtains among the embodiment 118] carbonyl }-furo [3,2-b] pyridin-3-yl) amino] carbonyl } cyclohexyl) the methyl carbamic acid tert-butyl ester (1.55g) is dissolved in the diox (10ml), to wherein adding 4N Yan Suan dioxane solution (20ml), and at room temperature stirred the mixture 12 hours.The concentrating under reduced pressure reaction soln is suspended in resistates in the ether.Filter collecting precipitation thing and dry, obtain title compound (1.49g).
APCI-MS M/Z：428/430[M+H] +。
Embodiment 120:(3-[(is trans-4-{[(2-{[(5-chloropyridine-2-yl) and amino]-carbonyl } furo [3,2-b] pyridin-3-yl) amino] carbonyl } cyclohexyl) (methyl)-amino] propyl group } t-butyl carbamate
N-(5-chloropyridine-2-yl)-3-({ [trans-4-(methylamino-)-cyclohexyl] carbonyl } amino) furo [3,2-b] the pyridine-2-carboxamide tri hydrochlorides (300mg) that obtain among the embodiment 119 are suspended in the chloroform (7ml).Under ice-cooled condition, in suspension, add 3-t-butoxycarbonyl amino propionic aldehyde (208mg) and triethylamine (334 μ l), wherein 3-t-butoxycarbonyl amino propionic aldehyde can be according to document (Synthesis, 1994,37) described method prepares by two-step reaction from the amino propionic aldehyde diethyl acetal of 3-.Mixture is stirred several minutes.After adding sodium triacetoxy borohydride (190mg), reaction soln is warmed to room temperature, and stirred 2 hours.In ice-cooled condition downhill reaction solution, pour saturated sodium bicarbonate aqueous solution into, the mixture chloroform extraction.Organic layer is water and saturated brine washing successively, dried over sodium sulfate, and solvent evaporated under reduced pressure.Resulting resistates NH-silica gel column chromatography (elutriant: ethyl acetate, follow by ethyl acetate/methanol=20/1) purifying, obtain title compound (291mg).
APCI-MS M/Z：585/587[M+H] +。
Embodiment 121:3-[({ is trans-the 4-[(3-aminopropyl) and (methyl) amino] cyclohexyl }-carbonyl) amino]-N-(5-chloropyridine-2-yl) furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194100961
With obtain among the embodiment 120 3-[(is trans-4-{[(2-{[(5-chloropyridine-2-yl) amino] carbonyl-furo [3,2-b] pyridin-3-yl) amino] carbonyl } cyclohexyl) (methyl) amino]-propyl group } t-butyl carbamate (265mg) is dissolved in the diox (3ml), to wherein adding 4N hydrochloric acid-dioxane solutions (6ml), at room temperature stirred the mixture 20 hours.The concentrating under reduced pressure reaction soln is suspended in resistates in the ether.Filter the collecting precipitation thing.Resulting solid suspension in chloroform, to wherein adding saturated sodium bicarbonate aqueous solution, is separated organic layer.Organic layer is washed with saturated brine, and dried over sodium sulfate, and solvent evaporated under reduced pressure obtain title compound (206mg).
APCI-MS M/Z：485/487[M+H] +。
Embodiment 122:3-[({ is trans-4-[[3-(kharophen) propyl group] and (methyl) amino]-cyclohexyl } carbonyl) amino]-N-(5-chloropyridine-2-yl) furo [3,2-b] pyridine-2-carboxamide
With the 3-[({ that obtains among the embodiment 121 trans-the 4-[(3-aminopropyl) (methyl) amino] cyclohexyl-carbonyl) amino]-N-(5-chloropyridine-2-yl) furo [3,2-b] pyridine-2-carboxamide (113mg) and triethylamine (65 μ l) be dissolved in the chloroform (5ml), under ice-cooled condition to wherein adding Acetyl Chloride 98Min. (25 μ l).Mixture is warmed to room temperature, and stirred 1 hour.In reaction soln, pour saturated sodium bicarbonate aqueous solution into, the mixture chloroform extraction.Organic layer is water and saturated brine washing successively, dried over sodium sulfate, and solvent evaporated under reduced pressure.Resulting resistates NH-silica gel column chromatography (elutriant: ethyl acetate, follow by ethyl acetate/methanol=10/1) purifying.Resulting solid suspension in normal hexane-Di Iso Propyl Ether, is filtered collection and obtains title compound (90mg).
APCI-MS M/Z：527/529[M+H] +。
Embodiment 123:6-(ethanoyl) amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194100972
6-amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(the 3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3 that obtains in employing and the embodiment 122 similar mode Processing Examples 103,2-b] pyridine-2-carboxamide (56mg), obtain title compound (39mg).
APCI-MS M/Z：555/557[M+H] +。
Embodiment 124:4-(trans-4-{[(2-{[(5-chloropyridine-2-yl) amino]-carbonyl } furo [3,2-b] pyridin-3-yl) amino] carbonyl } cyclohexyl)-3-oxo piperazine-1-carboxylic acid tert-butyl ester
Figure A20048000194100981
With trans-4-[4-(the tertbutyloxycarbonyl)-2-oxo piperazine-1-yl that obtains in the reference example 71] 3-amino-N-(5-chloropyridine-2-yl) furo [3 of acquisition in hexahydrobenzoic acid (370mg) and the reference example 24,2-b] pyridine-2-carboxamide (327mg) with and embodiment 118 similar modes handle, obtain title compound (151mg).
APCI-MS M/Z：597/599[M+H] +。
Embodiment 125:N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo piperazine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194100991
With 4-(trans-4-{[(2-{[(5-chloropyridine-2-yl) amino that obtains among the embodiment 124] carbonyl }-furo [3,2-b] pyridin-3-yl) amino] carbonyl } cyclohexyl)-3-oxo piperazine-1-carboxylic acid tert-butyl ester (220mg) handles with the mode that is similar to embodiment 121, obtains title compound (165mg).
APCI-MS M/Z：497/499[M+H] +。
Embodiment 126:N-(5-chloropyridine-2-yl)-3-({ [trans-4-(4-methyl-2-oxo piperazine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194100992
With N-(5-chloropyridine-2-yl)-3-({ [trans-4-(the 2-oxo piperazine-1-yl) cyclohexyl] carbonyl } amino) furo [3 that obtains among the embodiment 125,2-b] pyridine-2-carboxamide (60mg) and 35% formalin (19 μ l) handle with the mode that is similar to embodiment 120, obtains title compound (46mg).
APCI-MS M/Z：511/513[M+H] +。
Embodiment 127:3-({ [trans-4-(4-ethanoyl-2-oxo piperazine-1-yl) cyclohexyl]-carbonyl } amino)-N-(5-chloropyridine-2-yl) furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194101001
With N-(5-chloropyridine-2-yl)-3-({ [trans-4-(the 2-oxo piperazine-1-yl) cyclohexyl] carbonyl } amino) furo [3 that obtains among the embodiment 125,2-b] pyridine-2-carboxamide (50mg) and Acetyl Chloride 98Min. (9 μ l) handle with the mode that is similar to embodiment 122, obtains title compound (41mg).
APCI-MS M/Z：539/541[M+H] +。
Embodiment 128-138
Corresponding aminocompound and carboxylic acid cpd are handled with the mode that is similar to embodiment 2, obtained following compound.
Table 30
Figure A20048000194101011
Table 31
Table 32
Figure A20048000194101031
Embodiment 139:2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-{[5-(3-oxo morpholine-4-yl) pentanoyl] amino } furo [3,2-b] pyridine-5-carboxylic acid
Figure A20048000194101041
With the 2-{[(5-chloropyridine-2-yl that obtains among the embodiment 138) amino] carbonyl }-3-{[5-(3-oxo morpholine-4-yl) pentanoyl] amino } furo [3; 2-b] pyridine-5-carboxylate methyl ester (115mg) handles with the mode that is similar to embodiment 79, obtains title compound (94mg).
ESI-MS M/Z：514/516[M-H] -。
Embodiment 140:N 2-(5-chloropyridine-2-yl)-N 5-(methoxyethyl)-N 5-methyl-3-([5-(3-oxo morpholine-4-yl) pentanoyl] amino } furo [3,2-b] pyridine-2, the 5-diformamide
With the 2-{[(5-chloropyridine-2-yl that obtains among the embodiment 139) amino] carbonyl }-3-{[5-(3-oxo morpholine-4-yl) pentanoyl] amino } furo [3; 2-b] pyridine-5-carboxylic acid (82mg) and N-(2-methoxyethyl) methylamine (28mg) handle with the mode that is similar to embodiment 85, obtains title compound (70mg).
APCI-MS M/Z：587/589[M+H] +。
Embodiment 141:N-(5-picoline-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194101051
2-amino-5-picoline (81mg) is dissolved in the chloroform (5ml).Under ice-cooled condition, add 0.98M trimethyl aluminium-hexane solution (763 μ l), reaction soln was stirred 10 minutes under ice-cooled condition, at room temperature stirred then 0.5 hour.In resulting reaction soln, add 3-({ [trans-4-(the 3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3 that obtains in the reference example 79,2-b] pyridine-2-carboxylic acids methyl esters (150mg), mixture was at room temperature stirred 2 hours, under heating condition, stirred 5 hours down again at 50 ℃.The hydrochloric acid (3ml) of adding 10% stirred the mixture under the room temperature 0.5 hour in ice-cooled condition downhill reaction solution.Then reaction soln is neutralized with saturated sodium bicarbonate aqueous solution, and use chloroform extraction.Organic layer washs with saturated brine, dried over sodium sulfate, and solvent evaporated under reduced pressure.Resistates NH-silica gel column chromatography (elutriant: ethyl acetate, follow by ethyl acetate/methanol=10/1) purifying.Resulting solid suspension in ether, is filtered collection and obtains title compound (110mg).
APCI-MS M/Z：478[M+H] +。
Embodiment 142-145
Corresponding ester and aminocompound are handled with the mode that is similar to embodiment 141, obtained following compound.
Table 33
Figure A20048000194101061
Embodiment 146-149
Corresponding carboxylic acid and aminocompound are handled in the mode that is similar to embodiment 1 or embodiment 2, obtained following compound.
Table 34
Figure A20048000194101071
Embodiment 150,151
Corresponding ester is handled with the mode that is similar to embodiment 79, obtained following compound.
Table 35
Figure A20048000194101081
Embodiment 152,153
Corresponding carboxylic acid and aminocompound are handled with the mode that is similar to embodiment 85, obtained following compound.
Table 36
Figure A20048000194101091
Embodiment 154:N-(5-chloropyridine-2-yl)-4-methoxyl group-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-c] pyridine-2-carboxamide
With 3-amino-N-(5-chloropyridine-2-the yl)-4-methoxyl group furo [3 that obtains in the reference example 88,2-c] trans-4-tetramethyleneimine-1-basic ring cyclohexane carboxylic-acid hydrochloride (106mg) of obtaining in pyridine-2-carboxamide (82mg) and the reference example 10 handles with the mode that is similar to embodiment 2, obtains title compound (39mg).
APCI-MS M/Z：498/500[M+H] +。
Embodiment 155,156
With the 2-{[(5-chloropyridine-2-yl that obtains among the embodiment 81) amino] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-5-carboxylic acid and corresponding aminocompound handle with the mode that is similar to embodiment 85, obtains following compound.
Table 37
Embodiment 157-185
The corresponding aminocompound and the carboxylic acid cpd that obtain in the reference example are handled with the mode that is similar to embodiment 2, obtained following compound.
Table 38
Figure A20048000194101111
Table 39
Figure A20048000194101121
Table 40
Table 41
Figure A20048000194101141
Table 42
Table 43
Figure A20048000194101161
Table 44
Table 45
Embodiment 186-192
Corresponding ester and aminocompound are handled with the mode that is similar to embodiment 141, obtained following compound.
Table 46
Table 47
Figure A20048000194101201
Embodiment 193-202
The corresponding aminocompound and the corresponding carboxylic acid compound that obtain in reference example 24,87,90 and 91 are handled with the mode that is similar to embodiment 2, obtained following compound.
Table 48
Figure A20048000194101211
Table 49
Figure A20048000194101221
Table 50
Figure A20048000194101231
Embodiment 203,204
The ester and the aminocompound that obtain in the reference example 79 are handled with the mode that is similar to embodiment 141, obtained following compound.
Table 51
Embodiment 205:N-(3-amino-4-chloro-phenyl-)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide
With N-(4-chloro-3-nitrophenyl)-3-({ [trans-4-(the 3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3 that obtains among the embodiment 204,2-b] pyridine-2-carboxamide (50mg) is suspended in the ethanol (3ml), to wherein adding two hydration tin chlorides (II) (104mg).Mixture was at room temperature stirred 15 hours, stirred 5 hours down at 50 ℃ subsequently, stirred 7 hours down at 70 ℃ then.After cooling, saturated sodium bicarbonate aqueous solution and chloroform are poured in the reaction soln.Then, vigorous stirring mixture at room temperature.Separate organic layer, use dried over sodium sulfate, and reduction vaporization desolvates to remove.The resistates silica gel column chromatography (elutriant: chloroform, follow by chloroform/methanol=10/1) purifying.With resulting solid suspension in ether.Filter the collecting precipitation thing, obtain title compound (32mg).
APCI-MS M/Z：512/514[M+H] +。
Embodiment 206-208
The amine compound and the corresponding carboxylic acid that obtain in the reference example 125 are handled with the mode that is similar to embodiment 2, obtained following compound.
Table 52
Figure A20048000194101261
Embodiment 209-211
The compound that obtains among the embodiment 206-208 is handled with the mode that is similar to embodiment 79, obtained following compound.
Table 53
Figure A20048000194101271
Embodiment 212-214
The compound that obtains among the embodiment 209-211 is handled with the mode that is similar to embodiment 85, obtained following compound.
Table 54
Figure A20048000194101281
Embodiment 215-355
Adopt and the similar mode of the foregoing description, obtain following compound.
Table 55
Figure A20048000194101291
Table 56
Figure A20048000194101301
Table 57
Table 58
Figure A20048000194101321
Table 59
Table 60
Figure A20048000194101341
Table 61
Table 62
Figure A20048000194101361
Table 63
Table 64
Table 65
Figure A20048000194101391
Table 66
Table 67
Figure A20048000194101411
Table 68
Figure A20048000194101421
Table 69
Table 70
Figure A20048000194101441
Table 71
Figure A20048000194101451
Table 72
Figure A20048000194101461
Table 73
Reference example 1: trans-the 4-[(tertbutyloxycarbonyl) amino]-the hexahydrobenzoic acid methyl esters
(1) under-30 ℃, thionyl chloride (254ml) is added drop-wise in the methyl alcohol (1500ml), lasts about 1 hour.After adding, reaction mixture was at room temperature stirred 0.5 hour, to wherein adding trans-hexanaphthene-1,4-dicarboxylic acid (500.0g) at room temperature stirred mixture 17 hours then.The concentrating under reduced pressure reaction soln.Resistates dilutes with chloroform, and washs with saturated sodium bicarbonate aqueous solution and saturated brine.Organic layer dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.The crystallization in normal hexane of resulting resistates.Filter and collect product and dry, obtain trans-hexanaphthene-1,4-dimethyl dicarboxylate (545.0g).
APCI-MS M/Z：201[M+H] +。
(2) with the trans-hexanaphthene-1 that obtains in above-mentioned (1), 4-dimethyl dicarboxylate (150.0g) is dissolved in the tetrahydrofuran (THF) (1500ml), and drips the mixed solution of 28% sodium methylate/methyl alcohol (149g) and water (13.2g) under ice-cooled condition in solution.Reaction soln is warmed to room temperature, stirred 3.5 hours.Then to wherein pouring normal hexane (1500ml), filtering mixt, collecting precipitation thing into.Under ice-cooled condition, resulting solid is added in the mixed solution of concentrated hydrochloric acid (50ml), water (450ml) and chloroform (1000ml), and mixture was at room temperature stirred 20 minutes.Separate chloroform layer, the water layer chloroform extraction.Merge organic layer, use dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.The crystallization in normal hexane of resulting resistates is filtered and is collected and drying, obtains trans-4-(methoxycarbonyl) hexahydrobenzoic acid (106.0g).
ESI-MS M/Z：185[M-H] -。
(3) trans-4-(methoxycarbonyl) hexahydrobenzoic acid (100.0g) that obtains in above-mentioned (2) is dissolved in the trimethyl carbinol (1000ml), to wherein adding diphenylphosphine acylazide thing (155g) and triethylamine (78.6ml).Mixture was heated 1 hour down at about 60 ℃, and reheat refluxed 17 hours.After cooling, in reaction soln, add frozen water, the mixture ethyl acetate extraction.Organic layer washs dried over sodium sulfate, and solvent removed by evaporation at reduced pressure with saturated sodium bicarbonate aqueous solution and saturated brine.Resulting resistates is dissolved in the methyl alcohol (250ml),, under ice-cooled condition, stirs the mixture to wherein adding entry (750ml).0.5 after hour, filter the collecting precipitation thing, successively water/methyl alcohol (3: 1,1000ml) and normal hexane washing and dry, obtain title compound (117.0g).
APCI-MS M/Z：275[M+H] +。
Reference example 2: trans-4-(2-oxo-pyrrolidine-1-yl) hexanaphthene-carboxylic acid
(1) with the trans-4-[(tertbutyloxycarbonyl that obtains in the reference example 1) amino]-hexahydrobenzoic acid methyl esters (234.0g) is dissolved in the diox (500ml), to wherein adding 4N hydrochloric acid/diox (500ml), and at room temperature stirred the mixture 19 hours.The concentrating under reduced pressure reaction soln is suspended in resulting resistates in the ether.Filter the collecting precipitation thing, obtain trans-4-aminocyclohexane carboxylate methyl ester hydrochloride (121.9g).
APCI-MS M/Z：158[M+H] +
(2) trans-4-aminocyclohexane carboxylate methyl ester hydrochloride (45.31g) that obtains in above-mentioned (1) is suspended in the methylene dichloride (1000ml), under ice-cooled condition,, drip methylene dichloride (80ml) solution of triethylamine (81.5ml) subsequently to wherein adding 4-chlorobutanoylchloride (31.5ml).Reaction soln is warmed to room temperature, stirred 3 hours and concentrating under reduced pressure.In resulting resistates, pour ethyl acetate and 5% hydrochloric acid into, separate organic layer, with saturated sodium bicarbonate aqueous solution and saturated brine washing.The organic layer dried over sodium sulfate, and use activated carbon treatment, concentrating under reduced pressure filtrate.Resulting resistates is suspended in the diisopropyl ether.Filter collecting precipitation thing and dry, obtain trans-4-[(4-chlorobutyryl) amino] hexahydrobenzoic acid methyl esters (38.81g).
APCI-MS M/Z：262/264[M+H] +。
(3) 60% sodium hydride oil solution (9.60g) is suspended in N; in the N-N,N-DIMETHYLACETAMIDE (500ml), under ice-cooled condition, in mixed solution, add the trans-4-[(4-chlorobutyryl that obtains in above-mentioned (2) with the aliquot form) amino] hexahydrobenzoic acid methyl esters (52.32g).Reaction soln is warmed to room temperature, stirred 24 hours, then to wherein pouring saturated aqueous ammonium chloride and frozen water into.The reaction mixture chloroform extraction.Organic layer washs with saturated brine, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates is with silica gel column chromatography (elutriant: ethyl acetate) purifying, and resistates is suspended in normal hexane/Di Iso Propyl Ether.Filter and collect the crystal that produces, and drying obtains trans-4-(2-oxo-pyrrolidine-1-yl) hexahydrobenzoic acid methyl esters (39.20g).
APCI-MS M/Z：226[M+H] +。
(4) trans-4-(2-oxo-pyrrolidine-1-yl) the hexahydrobenzoic acid methyl esters (39.15g) that obtains in above-mentioned (3) is dissolved in the methyl alcohol (400ml), to wherein adding 2N aqueous sodium hydroxide solution (174ml).At room temperature stirred the mixture 3 hours.Hydrochloric acid with 10% under ice-cooled condition is adjusted to pH1-2 with reaction soln, and saturated with sodium-chlor, uses chloroform extraction subsequently.Organic layer dried over sodium sulfate, solvent removed by evaporation at reduced pressure then.Resulting resistates is suspended in a spot of ethyl acetate, to wherein pouring Di Iso Propyl Ether into.Filter and collect the crystal that produces, wash several times and drying, obtain title compound (35.94g) with Di Iso Propyl Ether.
ESI-MS M/Z：210[M-H] -。
Reference example 3: trans-4-[ethanoyl (methyl) amino] hexahydrobenzoic acid
Figure A20048000194101491
(1) with the trans-4-[(tertbutyloxycarbonyl that obtains in the reference example 1) amino] hexahydrobenzoic acid methyl esters (30.00g) is dissolved in N, in the dinethylformamide (150ml), and under ice-cooled condition to the sodium hydride oil solution (5.60g) that wherein adds 60%.After stirring 0.5 hour under the identical cooling conditions, in reaction soln, add methyl-iodide (14.5ml) and methyl alcohol (0.15ml) successively.Reaction soln is warmed to room temperature and stirred 4 hours.Under ice-cooled condition, in reaction soln, pour saturated aqueous ammonium chloride and frozen water into, and use the ethyl acetate extraction mixture.Organic layer is water and saturated brine washing successively, uses dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates obtains trans-4-[(tertbutyloxycarbonyl with silica gel column chromatography (elutriant: n-hexane/ethyl acetate=10/1 is 7/1 subsequently) purifying) (methyl) amino] hexahydrobenzoic acid methyl esters (26.33g).
APCI-MS M/Z：272[M+H] +。
(2) with the trans-4-[(tertbutyloxycarbonyl that obtains in above-mentioned (1)) (methyl) amino] hexahydrobenzoic acid methyl esters (26.32g) is dissolved in the diox (100ml), and to wherein adding 4N hydrochloric acid/dioxane solution (100ml).Reaction soln is at room temperature stirred 4 hours, and in solution, pour Di Iso Propyl Ether (500ml) into.Filter the collecting precipitation thing,, obtain trans-4-(methylamino-) hexahydrobenzoic acid methyl ester hydrochloride (19.01g) with Di Iso Propyl Ether washing and dry.
APCI-MS M/Z：172[M+H] +。
(3) trans-4-(methylamino-) the hexahydrobenzoic acid methyl ester hydrochloride (18.93g) that obtains in above-mentioned (2) is suspended in the methylene dichloride (400ml), and under ice-cooled condition, in solution, add Acetyl Chloride 98Min. (8.42ml), drip methylene dichloride (40ml) solution of triethylamine (38.1ml) subsequently.Reaction soln is warmed to room temperature, and stirred 2 hours.After adding 5% hydrochloric acid, with the mixture dichloromethane extraction.Organic layer washs with saturated brine, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates NH-silica gel column chromatography (elutriant: ethyl acetate) purifying obtains trans-4-[acetyl (methyl) amino] hexahydrobenzoic acid methyl esters (19.05g).
APCI-MS M/Z：214[M+H] +。
(4) with trans-4-[acetyl (methyl) amino that obtains in above-mentioned (3)] hexahydrobenzoic acid methyl esters (19.00g) is dissolved in the methyl alcohol (200ml), and to wherein adding 2N aqueous sodium hydroxide solution (60ml).At room temperature stirred the mixture then 3 hours.Under ice-cooled condition, by adding 10% hydrochloric acid, reaction soln is adjusted to pH1-2, saturated with sodium-chlor, use chloroform extraction then.Organic layer dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates is suspended in a spot of ethyl acetate, and in mixture, pours Di Iso Propyl Ether into.Filter and collect crystal, also dry several times with the Di Iso Propyl Ether washing, obtain title compound (16.31g).
ESI-MS M/Z：198[M-H] -。
Reference example 4: trans-4-(3-oxo morpholine-4-yl) hexanaphthene-carboxylic acid
Figure A20048000194101511
(1) 60% sodium hydride oil solution (6.80g) is suspended in the N,N-dimethylacetamide (80ml), under ice-cooled condition, in mixed solution, drips N,N-dimethylacetamide (50ml) solution of 2-(benzyloxy) ethanol (12.9g), last 10 minutes.After at room temperature stirring 15 minutes, use ice-cooled reaction soln, and to wherein adding Mono Chloro Acetic Acid (8.13g) with the aliquot form.At room temperature stirred the mixture then 11 hours.The concentrating under reduced pressure reaction soln adds sodium bicarbonate aqueous solution in resulting resistates, mixture washs with ether.Ethyl acetate extraction is used in water layer concentrated hydrochloric acid acidifying then.Organic layer washs with saturated brine, and dried over sodium sulfate, and solvent removed by evaporation at reduced pressure obtain [2-(benzyloxy) oxyethyl group] acetate (18.24g).
ESI-MS M/Z：209[M-H] -。
(2) with 2-(benzyloxy) oxyethyl group that obtains in above-mentioned (1)] trans-4-aminocyclohexane carboxylate methyl ester hydrochloride (5.27g) and the I-hydroxybenzotriazoles (5.06g) that obtain in the acetate (6.51g), reference example 2 (1) are dissolved in N, in the dinethylformamide (100ml).Under ice-cooled condition, in mixture, add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (7.10g) and triethylamine (4.50ml) successively, and at room temperature stirred the mixture 3 days.The concentrating under reduced pressure reaction soln adds sodium bicarbonate aqueous solution in resulting resistates, use ethyl acetate extraction subsequently.Organic layer washs with saturated brine, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates silica gel column chromatography (elutriant: hexane/ethyl acetate=1: 1, use ethyl acetate subsequently) purifying, obtain trans-4-({ [2-(2-benzyloxy) oxyethyl group] ethanoyl } amino) hexahydrobenzoic acid methyl esters (8.24g).
APCI-MS M/Z：350[M+H] +。
(3) trans-4-({ [2-(2-benzyloxy) oxyethyl group] ethanoyl } amino) the hexahydrobenzoic acid methyl esters (5.09g) that obtains in above-mentioned (2) is dissolved in the acetate (150ml); to wherein adding 5% palladium-carbon (1.01g); under normal pressure; in hydrogen atmosphere, mixture was at room temperature stirred 2.4 hours.Filtering reacting solution is removed catalyzer, concentrating under reduced pressure filtrate.Resulting resistates is dissolved in the chloroform, and with saturated sodium bicarbonate aqueous solution washing, dried over sodium sulfate, and evaporation obtains trans-4-{[(2-hydroxyl-oxethyl except that desolvating) ethanoyl] amino } hexahydrobenzoic acid methyl esters (3.32g).
APCI-MS M/Z：260[M+H] +。
(4) with the trans-4-{[(2-hydroxyl-oxethyl that obtains in above-mentioned (3)) ethanoyl] amino hexahydrobenzoic acid methyl esters (1.37g) is dissolved in the chloroform (15ml), under ice-cooled condition to wherein adding triethylamine (890 μ l).Under uniform temp, drip methylsulfonyl chloride (450 μ l) then.Reaction soln was stirred 3 hours under ice-cooled condition, dilute with water, and use chloroform extraction.Organic layer washs with saturated brine, and dried over sodium sulfate, and solvent removed by evaporation at reduced pressure obtain trans-4-[({2-[(methylsulfonyl) the oxygen base] oxyethyl group } ethanoyl) amino]-hexahydrobenzoic acid methyl esters (1.83g).
APCI-MS M/Z：338[M+H] +。
(5) with the trans-4-[({2-[(methylsulfonyl that obtains in above-mentioned (4)) the oxygen base] oxyethyl group } ethanoyl) amino]-hexahydrobenzoic acid methyl esters (1.08g) is dissolved in N; in the N-N,N-DIMETHYLACETAMIDE (15ml); under ice-cooled condition, to wherein adding 60% sodium hydride oil solution (135mg), and at room temperature stirred the mixture 16 hours.The concentrating under reduced pressure reaction soln adds entry and excessive sodium-chlor in resulting resistates, then use chloroform extraction.Organic layer dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates silica gel column chromatography (elutriant: hexane/ethyl acetate=1: 1, follow by ethyl acetate) purifying, obtain trans-4-(3-oxo morpholine-4-yl) hexahydrobenzoic acid methyl esters (715mg).
APCI-MS M/Z：242[M+H] +。
(6) trans-4-(3-oxo morpholine-4-yl) the hexahydrobenzoic acid methyl esters (500mg) that obtains in above-mentioned (5) is handled with the mode that is similar to reference example 2 (4), obtained title compound (322mg).
ESI-MS M/Z：226[M-H] -。
Reference example 5: trans-4-(2-oxo-1,3-oxazolidine-3-yl) hexanaphthene-carboxylic acid
(1) trans-4-aminocyclohexane carboxylate methyl ester hydrochloride (5.00g) that obtains in the reference example 2 (1) is dissolved in the chloroform (60ml), under ice-cooled condition,, drip chloroform (10ml) solution of 2-chloroethyl carbonochloridic acid ester (3.3ml) subsequently to wherein adding triethylamine (11ml).After at room temperature stirring 2.5 hours, in reaction soln, add 5% hydrochloric acid, and use the chloroform extraction mixture.Organic layer washs with saturated brine, dried over sodium sulfate, solvent removed by evaporation at reduced pressure then.Resulting resistates is suspended in chloroform/Di Iso Propyl Ether.Filter collecting precipitation thing and dry, obtain trans-4-{[(2-chloroethoxy) carbonyl] amino } hexahydrobenzoic acid methyl esters (5.11g).
APCI-MS M/Z：264/266[M+H] +。
(2) with the trans-4-{[(2-chloroethoxy that obtains in above-mentioned (1)) carbonyl] amino hexahydrobenzoic acid methyl esters (3.70g) is dissolved in the N,N-dimethylacetamide (50ml), under ice-cooled condition to wherein adding 60% sodium hydride oil solution (630mg).At room temperature stirred the mixture then 16.5 hours.In reaction soln, add entry, and use the ethyl acetate extraction mixture.Dried over sodium sulfate is used in organic layer water and saturated brine washing then.Solvent removed by evaporation at reduced pressure, and resulting resistates silica gel column chromatography (elutriant: hexane/ethyl acetate=1/1, then use ethyl acetate) purifying, obtain trans-4-(2-oxo-1,3-oxazolidine-3-yl) hexahydrobenzoic acid methyl esters (1.83g).
APCI-MS M/Z：228[M+H] +。
(3) trans-4-(2-oxo-1,3-oxazolidine-3-yl) the hexahydrobenzoic acid methyl esters (1.84g) that obtains in above-mentioned (2) is handled with the mode that is similar to reference example 2 (4), obtained title compound (1.75g).
ESI-MS M/Z：212[M-H] -。
Reference example 6:5-(2-oxo-pyrrolidine-1-yl) valeric acid
Figure A20048000194101531
(1) 5-aminovaleric acid (7.35g) is dissolved in the methyl alcohol (50ml), under ice-cooled condition to thionyl chloride (4.9ml) wherein.Then reaction soln is warmed to room temperature, stirred 17 hours.The concentrating under reduced pressure reaction soln.Resulting resistates is suspended in the ether, filters the collecting precipitation thing, obtain 5-aminovaleric acid methyl ester hydrochloride (9.93g).
APCI-MS M/Z：132[M+H] +。
(2) the 5-aminovaleric acid methyl ester hydrochloride (1.68g) that obtains in above-mentioned (1) is suspended in the chloroform (20ml), under ice-cooled condition, in suspension, adds triethylamine (2.54g), drip 4-chlorobutanoylchloride (1.55g) subsequently.Reaction soln is warmed to room temperature, stirred 2 hours.Frozen water is poured in the reaction soln, used the chloroform extraction mixture.Organic layer is used dried over sodium sulfate then with 10% hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated brine washing.Solvent removed by evaporation at reduced pressure obtains the 5-[(4-chlorobutyryl) amino]-methyl valerate (2.34g).
APCI-MS M/Z：236/238[M+H] +。
(3) with the 5-[(4-chlorobutyryl that obtains in above-mentioned (2)) amino]-methyl valerate (2.33g) is dissolved in the N,N-dimethylacetamide (20ml), under ice-cooled condition 60% sodium hydride oil solution (0.47g) is divided into aliquot and joins in the solution.Reaction soln is warmed to room temperature, stirred 20 hours, and solvent removed by evaporation at reduced pressure.Resulting resistates silica gel column chromatography (elutriant: chloroform, then with chloroform/ethyl acetate=20/1) purifying, obtain 5-(2-oxo-pyrrolidine-1-yl) methyl valerate (2.15g).
APCI-MS M/Z：200[M+H] +。
(4) 5-(2-oxo-pyrrolidine-1-yl) methyl valerate (1.00g) that obtains in above-mentioned (3) is dissolved in the methyl alcohol (20ml), to the aqueous sodium hydroxide solution that wherein adds 4N (2.5ml).Reaction soln is warmed to room temperature, stirred 18 hours.With ether washing reaction solution, to the hydrochloric acid that wherein adds 2N (5.0ml), concentrating under reduced pressure subsequently.Resulting resistates chloroform extraction, dried over sodium sulfate.Solvent removed by evaporation at reduced pressure obtains title compound (0.90g).
ESI-MS M/Z：184[M-H] -。
Reference example 7:5-(3-oxo morpholine-4-yl) valeric acid
Figure A20048000194101541
(1) 5-aminovaleric acid methyl ester hydrochloride (3.35g), reference example 4 (1) middle [2-(benzyloxy) oxyethyl group] acetate (4.63g) and the I-hydroxybenzotriazoles (3.78g) that obtain that obtain in the reference example 6 (1) is dissolved in N, in the dinethylformamide (80ml).Under ice-cooled condition, in mixture, add 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (5.37g) and triethylamine (3.35ml) successively, and mixture was at room temperature stirred 2 days.The concentrating under reduced pressure reaction soln, resulting resistates dilutes with frozen water, and uses ethyl acetate extraction.Organic layer washs successively with saturated sodium bicarbonate aqueous solution, water and saturated brine, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates silica gel column chromatography (elutriant: hexane/ethyl acetate=1: 1, then use ethyl acetate) purifying, obtain 5-({ [2-(benzyloxy) oxyethyl group] ethanoyl } amino) methyl valerate (5.56g).
APCI-MS M/Z：324[M+H] +。
(2) 5-({ [2-(benzyloxy) oxyethyl group] ethanoyl } amino) methyl valerate (5.54g) that obtains in above-mentioned (1) is dissolved in the tetrahydrofuran (THF) (60ml), and carries palladium hydroxide (0.5g) to the carbon that wherein adds 20%.Under normal pressure, under nitrogen atmosphere, mixture was at room temperature stirred 4 hours then.Filtering reacting solution is removed catalyzer, and concentrating under reduced pressure filtrate obtains the 5-{[(2-hydroxyl-oxethyl then) ethanoyl] amino } methyl valerate (3.76g).
APCI-MS M/Z：234[M+H] +。
(3) with the 5-{[(2-hydroxyl-oxethyl that obtains in above-mentioned (2)) ethanoyl] amino methyl valerate (1.17g) is dissolved in the chloroform (15ml), under ice-cooled condition to wherein adding triethylamine (0.84ml).Under uniform temp, methylsulfonyl chloride (0.43ml) is added drop-wise in the mixture then.Reaction soln is warmed to room temperature, stirred 1 hour, then frozen water is poured into wherein, use chloroform extraction subsequently.Organic layer washs with saturated brine, and dried over sodium sulfate, and solvent removed by evaporation at reduced pressure obtain the 5-[({2-[(methylsulfonyl) the oxygen base] oxyethyl group }-ethanoyl) amino] methyl valerate (1.51g).
APCI-MS M/Z：312[M+H] +。
(4) with the 5-[({2-[(methylsulfonyl that obtains in above-mentioned (3)) the oxygen base] oxyethyl group }-ethanoyl) amino] methyl valerate (1.48g) is dissolved in N; in the N-N,N-DIMETHYLACETAMIDE (22ml), under ice-cooled condition to wherein adding 60% sodium hydride oil solution (0.20g).At room temperature stirred the mixture then 18 hours.Frozen water is poured in the reaction soln, and used the chloroform extraction mixture.Organic layer washs with saturated brine, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates obtains 5-(3-oxo morpholine-4-yl) methyl valerate (0.93g) with silica gel column chromatography (elutriant: hexane/ethyl acetate=1/1 then is an ethyl acetate) purifying.
APCI-MS M/Z：216[M+H] +。
(5) 5-(the 3-oxo morpholine-4-yl) methyl valerate (500mg) that obtains in above-mentioned (4) is dissolved in the methyl alcohol (10ml), to the aqueous solution that wherein adds sodium hydroxide (0.40g) (2ml).Then reaction soln is warmed to room temperature, and stirred 17 hours.With the reaction soln concentrating under reduced pressure, with the neutralization of 2N hydrochloric acid, concentrating under reduced pressure again.Resulting resistates chloroform extraction, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure obtain title compound (0.35g).
ESI-MS M/Z：200[M-H] -。
Reference example 8: trans-4-(dimethylamino) hexahydrobenzoic acid hydrochloride
Figure A20048000194101561
(1) trans-4-aminocyclohexane carboxylate methyl ester hydrochloride (93.0g) that obtains in the reference example 2 (1) is dissolved in the methyl alcohol (1000ml), and to the formalin (95.4ml), sodium acetate (39.4g) and the 10% palladium/carbon (10g) that wherein add 35%.Under atmospheric hydrogen pressure, mixture was at room temperature stirred 3.5 hours then.Remove by filter insoluble substance, concentrating under reduced pressure filtrate.In resulting resistates, pour 20% wet chemical (500ml) into, use the chloroform extraction mixture.Organic layer sodium sulfate and salt of wormwood drying, and solvent removed by evaporation at reduced pressure.(elutriant: n-hexane/ethyl acetate=2/1) purifying obtains trans-4-dimethylamino hexahydrobenzoic acid methyl esters (87.3g) to resulting resistates with the NH-silica gel column chromatography.
APCI-MS M/Z：186[M+H] +
(2) trans-4-(dimethylamino) the hexahydrobenzoic acid methyl esters (27.6g) that obtains in above-mentioned (1) is dissolved in diox (300ml) and the water (100ml), to the hydrochloric acid that wherein adds 6N (50ml).Mixture heating up was refluxed 4 hours.In mixture, add 6N hydrochloric acid (50ml) again, again with reaction mixture reflux 1 hour.The concentrating under reduced pressure reaction soln carries out component distillation with toluene.Resulting resistates is suspended in the Di Iso Propyl Ether.Filter the collecting precipitation thing,, obtain title compound (27.5g) with Di Iso Propyl Ether washing and dry.
APCI-MS M/Z：172[M+H] +。
Reference example 9: trans-the 4-[(dimethylamino) methyl] the hexahydrobenzoic acid hydrochloride
Figure A20048000194101562
(1) trans-4-(aminomethyl) hexahydrobenzoic acid (6.29g) is suspended in the methyl alcohol (32ml), under ice-cooled condition to thionyl chloride (6ml) wherein.Reaction soln is warmed to room temperature, and stirring is spent the night, and is evaporated to drying, obtains trans-4-(aminomethyl)-hexahydrobenzoic acid methyl ester hydrochloride (8.69g).
APCI-MS M/Z：172[M+H] +。
(2) trans-4-(the aminomethyl)-hexahydrobenzoic acid methyl ester hydrochloride (8.69g) that obtains in above-mentioned (1) is suspended in the methylene dichloride (400ml), to wherein adding triethylamine (11.2ml).Then mixture is at room temperature stirred several minutes, under ice-cooled condition to the formalin (15.9ml) and the sodium triacetoxy borohydride (25.43g) that wherein add 35%.Reaction soln is warmed to room temperature and stirred 2 hours.Saturated sodium bicarbonate aqueous solution is poured in the solution, used the chloroform extraction mixture.Organic layer water and saturated brine wash successively, use dried over sodium sulfate.Solvent evaporated under reduced pressure obtains trans-4-[(dimethylamino) methyl]-hexahydrobenzoic acid methyl esters (7.42g).
APCI-MS M/Z：200[M+H] +。
(3) with trans-4-(dimethylamino) methyl that obtains in above-mentioned (2)]-hexahydrobenzoic acid methyl esters (7.41g) is dissolved in the diox (140ml), to the hydrochloric acid that wherein adds 2N (70ml).Then mixture heating up was refluxed 3 hours.After cooling, concentrating under reduced pressure reaction soln.Resulting resistates carries out component distillation with toluene, and dry resulting product obtains title compound (8.45g).
APCI-MS M/Z：186[M+H] +。
Reference example 10: trans-the 4-tetramethyleneimine-1-basic ring cyclohexane carboxylic-acid hydrochloride
With the trans-4-aminocyclohexane carboxylate methyl ester hydrochloride (10g), 1 that obtains in the reference example 2 (1), 4-two butyl iodides (19.2g) and yellow soda ash (16.4g) are suspended in tetrahydrofuran (THF) (300ml) and N, in the mixed solution of N-N,N-DIMETHYLACETAMIDE (60ml), and mixture stirred 20 hours down at 70 ℃.The concentrating under reduced pressure reaction soln.Resistates is dissolved in ethyl acetate/water, and separates organic layer.Organic layer water and saturated brine washing, dried over sodium sulfate and solvent removed by evaporation at reduced pressure.(elutriant: ethyl acetate/hexane=1/5) purifying obtains trans-4-tetramethyleneimine-1-basic ring cyclohexane carboxylic-acid methyl esters (10.9g) to resulting resistates with the NH-silica gel column chromatography.
APCI-MS M/Z：212[M+H] +。
(2) add 2N hydrochloric acid (80ml) in diox (150ml) solution of the trans-4-tetramethyleneimine-1-basic ring cyclohexane carboxylic-acid methyl esters (10.9g) that in above-mentioned (1), obtains, mixture was stirred 3 hours down at 110 ℃, evaporate methyl alcohol simultaneously.The concentrating under reduced pressure reaction soln.Resulting resistates is suspended in the ether, filters collection and obtain title compound (11.1g).
APCI-MS M/Z：198[M+H] +。
Reference example 11: trans-the 4-morpholine-4-basic ring cyclohexane carboxylic-acid hydrochloride
(1) trans-4-aminocyclohexane carboxylate methyl ester hydrochloride (47.5g), two (2-chloroethyl) ethers (34.5ml), yellow soda ash (77.9g) and the sodium iodide (88g) that obtains in the reference example 2 (1) is suspended in the mixed solution of tetrahydrofuran (THF) (1400ml) and N,N-dimethylacetamide (280ml).Then mixture heating up was refluxed 18 hours.Two (2-chloroethyl) ethers (23ml) and sodium iodide (22g) are added in the reaction soln, again mixture were refluxed 6 hours.The concentrating under reduced pressure reaction soln.Resistates is dissolved in ethyl acetate/water, separates organic layer.Organic layer water and saturated brine washing, dried over sodium sulfate and solvent removed by evaporation at reduced pressure.Resulting resistates obtains trans-4-morpholine-4-basic ring cyclohexane carboxylic-acid methyl esters (53.9g) with NH-silica gel column chromatography (elutriant: ethyl acetate/hexane=1/30 then is ethyl acetate/hexane=1/5, is 1/3 then) purifying.
APCI-MS M/Z：228[M+H] +。
(2) add 2N hydrochloric acid (400ml) in diox (750ml) solution of the trans-4-morpholine-4-basic ring cyclohexane carboxylic-acid methyl esters (53.8g) that in above-mentioned (1), obtains, mixture was stirred 4 hours down at 110 ℃, evaporate methyl alcohol simultaneously.Concentrated reaction solution.Resulting resistates is suspended in the ether, filters collection and obtain title compound (54.8g).
APCI-MS M/Z：214[M+H] +。
Reference example 12: trans-the 4-[(tertbutyloxycarbonyl) (methyl) amino]-hexahydrobenzoic acid
With the trans-4-[(tertbutyloxycarbonyls that obtain in the reference example 3 (1)) (methyl) amino] hexahydrobenzoic acid methyl esters (44.78g) is dissolved in the methyl alcohol (300ml), to the aqueous sodium hydroxide solution that wherein adds 2N (100ml).At room temperature stirred the mixture then 6 hours.The concentrating under reduced pressure reaction soln.Under ice-cooled condition, in resistates, add the hydrochloric acid of frozen water, ethyl acetate and 10%, and use the ethyl acetate extraction mixture.Organic layer water and saturated brine wash successively, dried over sodium sulfate and solvent removed by evaporation at reduced pressure.Resulting resistates is suspended in the amount of ethyl acetate, in mixture, pours normal hexane into.Filter and collect the crystal that obtains, also dry several times with normal hexane/Di Iso Propyl Ether washing, obtain title compound (39.20g).
ESI-MS M/Z：256[M-H] -。
Reference example 13:[is trans-4-(dimethylamino) cyclohexyl] and acetic acid hydrochloride
(1) potassium hydroxide (12.8g) is dissolved in the water (30ml), to wherein adding ether (45ml).In resulting mixture, adding N-nitroso-group-N-methylurea (5.07g) under the ice-cooled condition.Stirring reaction solution is 10 minutes under identical cooling conditions, separates organic layer and uses the potassium hydroxide drying, obtains the diethyl ether solution of diazomethane.
Under argon atmospher, with the trans-4-[(tertbutyloxycarbonyl that obtains in the reference example 12) amino]-hexahydrobenzoic acid (3.0g) is suspended in the ether (40ml), under-10 ℃,, drip the chloroformic acid tert-butyl ester (1.75ml) subsequently to wherein adding triethylamine (1.89ml).Reaction soln was stirred 30 minutes down at-10 ℃, and under-10 ℃, the diethyl ether solution of diazomethane is added drop-wise in the reaction soln.Then reaction soln is warming to room temperature, and stirred 15 hours.Down 10% aqueous citric acid solution is poured in the solution ice-cooled, separated organic layer.Organic layer is washed dried over sodium sulfate, and solvent removed by evaporation at reduced pressure with saturated sodium bicarbonate aqueous solution, water and saturated brine.Resulting resistates silica gel column chromatography (elutriant: ethyl acetate/hexane=1/3, use ethyl acetate/hexane=1/2 subsequently) purifying, obtain [trans-4-(2-diazonium ethanoyl) cyclohexyl] t-butyl carbamate (1.86g).
APCI-MS M/Z：285[M+NH 4] +。
(2) under argon atmospher, in fast light reactor, [trans-4-(2-diazonium ethanoyl) cyclohexyl] t-butyl carbamate (1.62g) that obtains in above-mentioned (1) is dissolved in the methyl alcohol (30ml), mixture is cooled to-25 ℃.Triethylamine (2.4ml) solution that adds silver benzoate (153mg) in reaction soln is warmed to room temperature with mixture and stirred 3 hours.The concentrating under reduced pressure reaction soln.Resulting resistates is dissolved in the ethyl acetate, successively with saturated sodium bicarbonate aqueous solution, saturated aqueous ammonium chloride and saturated brine washing.The mixture dried over sodium sulfate, evaporation removes and desolvates, and obtains { trans-[4-(N-tertbutyloxycarbonyl) amino] cyclohexyl } methyl acetate (1.25g).
APCI-MS M/Z：289[M+NH 4] +。
(3) 1 of { trans-[4-(N-tertbutyloxycarbonyl) amino] cyclohexyl } methyl acetate (1.23g) that in (2), obtains, add 4N hydrochloric acid/dioxane solution (8ml) in 4-diox (8ml) solution, at room temperature stirred the mixture 5 hours.The concentrating under reduced pressure reaction soln obtains (trans-the 4-aminocyclohexyl) methyl acetate hydrochloride (898mg) to dry.
APCI-MS M/Z：172[M+H] +。
(4) under ice-cooled condition, triethylamine (1.2ml) is added in methylene dichloride (30ml) suspension of (trans-the 4-aminocyclohexyl) the methyl acetate hydrochloride (895mg) that obtains in above-mentioned (3), stir the mixture.Under ice-cooled condition, add 35% formalin (1.71ml) and sodium triacetoxy borohydride (2.74g) then successively.Reaction soln is warmed to room temperature, and stirred 6 hours.Under ice-cooled condition, pour saturated sodium bicarbonate aqueous solution into, and use the chloroform extraction mixture.Organic layer washs with saturated brine, dried over sodium sulfate.Solvent removed by evaporation at reduced pressure obtains [trans-4-(dimethylamino) cyclohexyl] methyl acetate (771mg).
APCI-MS M/Z：200[M+H] +。
(5) add 1N hydrochloric acid (15ml), reflux mixture 3 hours in diox (25ml) solution of [trans-4-(dimethylamino) cyclohexyl] methyl acetate (760mg) that in above-mentioned (4), obtains.The concentrating under reduced pressure reaction soln is suspended in resulting resistates in the ether.Filter collecting precipitation thing and dry, obtain title compound (795mg).
APCI-MS M/Z：186[M+H] +。
Reference example 14: piperidin-4-yl ethyl acetate hydrochloride
Figure A20048000194101611
(pyridin-4-yl) ethyl acetate (50.00g) is dissolved in the acetate (500ml), to wherein adding platinum oxide (3.44g).Under the nitrogen atmosphere of 55psi, mixture is at room temperature vibrated 20 hours.Remove by filter insolubles, concentrating under reduced pressure filtrate.Resulting resistates is dissolved in the diox (200ml), to wherein adding 4N hydrochloric acid/diox (400ml).The reduction vaporization mixture desolvates to remove then.Resulting resistates is suspended in ether/Di Iso Propyl Ether, filters the collecting precipitation thing.Gains obtain title compound (61.80g) with Di Iso Propyl Ether washing and dry.
APCI-MS M/Z：172[M+H] +。
Reference example 15:(1-sec.-propyl piperidin-4-yl) acetic acid hydrochloride
Figure A20048000194101612
(1) (piperidin-4-yl) ethyl acetate hydrochloride (11.12g) that obtains in the reference example 14 is dissolved in the ethanol (150ml), to wherein adding 2-iodo propane (6.4ml) and salt of wormwood (22.2g).Then mixture heating up is refluxed and spend the night.Remove by filter insolubles, concentrating under reduced pressure filtrate.Resistates dilutes with chloroform, water and saturated brine washing successively, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.(elutriant: n-hexane/ethyl acetate=10/1) purifying obtains (1-sec.-propyl-piperidin-4-yl) ethyl acetate (9.87g) to resulting resistates with the NH-silica gel column chromatography.
APCI-MS M/Z：214[M+H] +。
(2) add entry (33ml) and concentrated hydrochloric acid (66ml) in (1-sec.-propyl-piperidin-4-yl) ethyl acetate (9.77g) that in above-mentioned (1), obtains, and mixture heating up was refluxed 24 hours.The concentrating under reduced pressure reaction soln, resistates carries out component distillation with toluene.Filter and collect resulting resistates, dry then with the Di Iso Propyl Ether washing, obtain title compound (9.76g).
APCI-MS M/Z：186[M+H] +。
Reference example 16:1-sec.-propyl piperidines-4-carboxylic acid hydrochloride
Piperidines-4-carboxylic acid, ethyl ester is handled with the mode that is similar to reference example 15, obtained title compound.
APCI-MS M/Z：172[M+H] +。
Reference example 17:1-pyridin-4-yl piperidines-4-carboxylic acid
Figure A20048000194101622
4-chloropyridine hydrochloride (9.55g) and triethylamine (26.0ml) are dissolved in ethanol (10ml) and the water (30ml), to wherein adding iso ethyl nicotinate (10.00g).In sealed tube, reaction soln was heated 96 hours down at 150 ℃ then.After cooling, ethanol is added in the reaction soln, removes by filter insolubles.Concentrating under reduced pressure filtrate is suspended in resulting resistates in the chloroform.Filter the collecting precipitation thing, at water/N, recrystallization in the dinethylformamide obtains title compound (10.34g).
APCI-MS M/Z：207[M+H] +。
Reference example 18: trans-4-(4-oxo-1,3-oxazolidine-3-yl) hexahydrobenzoic acid
Figure A20048000194101623
(1) under ice-cooled condition, 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (742mg) and I-hydroxybenzotriazole (523mg) are added to the N of the trans-4-aminocyclohexane carboxylate methyl ester hydrochloride (500mg), triethylamine (540 μ l) and the oxyacetic acids (295mg) that obtain in the reference example 2 (1), in dinethylformamide (10ml) solution.Then mixture was at room temperature stirred 15 hours.Concentrated reaction solution is poured saturated sodium bicarbonate solution wherein into, then uses chloroform extraction.Organic layer dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.(elutriant: chloroform～methyl alcohol/chloroform=1/20) purifying obtains trans-4-(glycolyl amino) hexahydrobenzoic acid methyl esters (602mg) to resulting resistates with silica gel column chromatography.
APCI-MS M/Z：216[M+H] +。
(2) trans-4-(glycolyl amino) hexahydrobenzoic acid methyl esters (280mg), paraformaldehyde (280mg) and a hydration tosic acid (45mg) that obtains in above-mentioned (1) is added in the toluene (5ml), and stirred 4 hours down at 100 ℃.After cooling, saturated sodium bicarbonate aqueous solution is poured in the reaction soln, and used the ethyl acetate extraction mixture.Organic layer water and saturated brine washing, dried over sodium sulfate and solvent removed by evaporation at reduced pressure.(elutriant: ethyl acetate/hexane=1/1～ethyl acetate) purifying obtains trans-4-(4-oxo-1,3-oxazolidine-3-yl) hexahydrobenzoic acid methyl esters (190mg) to resulting resistates with silica gel column chromatography.
APCI-MS M/Z：228[M+H] +。
(3) add 1N aqueous sodium hydroxide solution (2.9ml) in methyl alcohol (5ml) solution of trans-4-(4-oxo-1,3-oxazolidine-3-yl) the hexahydrobenzoic acid methyl esters (330mg) that in above-mentioned (2), obtains.Under the greenhouse, stirred the mixture 3 hours then.Concentrated reaction solution is used the 2N hcl acidifying, and to wherein adding sodium-chlor, then uses chloroform extraction.The organic layer dried over sodium sulfate, solvent removed by evaporation at reduced pressure.Resulting resistates is suspended in the ether, filters collection and obtain title compound (288mg).
ESI-MS M/Z：221[M-H] -。
Reference example 19: trans-4-(4-oxo-1,3-oxazine alkane-3-yl) hexahydrobenzoic acid
(1) under ice-cooled condition, the N of the trans-4-aminocyclohexane carboxylate methyl ester hydrochloride (1.0g) that in reference example 2 (1), obtains, triethylamine (1.1ml), 30% the 3-hydroxy-propionic acid aqueous solution (1.86ml), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.19g) and I-hydroxybenzotriazole (837mg) in dinethylformamide (15ml) solution, then mixture was at room temperature stirred 20 hours.Concentrated reaction solution is poured saturated sodium bicarbonate aqueous solution in resistates, use chloroform extraction subsequently.The organic layer dried over sodium sulfate, and evaporation is except that desolvating.Resulting resistates silica gel column chromatography (elutriant: ethyl acetate) purifying obtains trans-4-[(3-hydroxyl propionyl) amino] hexahydrobenzoic acid methyl esters (534mg).
APCI-MS M/Z：230[M+H] +。
(2) with the trans-4-[(3-hydroxyl propionyl that obtains in above-mentioned (1)) amino] hexahydrobenzoic acid methyl esters (530mg), paraformaldehyde (530mg) and a hydration tosic acid (85mg) be added in the toluene (10ml), and stirred the mixture under 100 ℃ 4 hours.After cooling, saturated sodium bicarbonate aqueous solution and ethyl acetate are poured in the mixed solution into the filtering separation insolubles.The organic layer of separating filtrate, and use the ethyl acetate extraction water layer.Merge organic layer, water and saturated brine washing, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.(elutriant: ethyl acetate) purifying obtains trans-4-(4-oxo-1,3-oxazine alkane-3-yl) hexahydrobenzoic acid methyl esters (306mg) to resulting resistates with silica gel column chromatography.
APCI-MS M/Z：242[M+H] +。
(3) add 1N aqueous sodium hydroxide solution (2.5ml) in methyl alcohol (5ml) solution of trans-4-(4-oxo-1,3-oxazine alkane-3-yl) the hexahydrobenzoic acid methyl esters (300mg) that in above-mentioned (2), obtains.Under the greenhouse, stirred the mixture 4 hours then.Concentrated reaction solution is used the 2N hcl acidifying, and to wherein adding sodium-chlor, then uses chloroform extraction.The organic layer dried over sodium sulfate, solvent removed by evaporation at reduced pressure.Resulting resistates is suspended in the ether, filters collection and obtain title compound (252mg).
ESI-MS M/Z：226[M-H] -。
Reference example 20: trans-4-(1,1-dioxy isothiazolidine-2-yl) hexahydrobenzoic acid
Figure A20048000194101641
(1) trans-4-aminocyclohexane carboxylate methyl ester hydrochlorides (4.08g) that obtain in the reference example 2 (1) are suspended in the chloroform (50ml), under ice-cooled condition to wherein adding triethylamine (8.8ml).Subsequently, under uniform temp, drip chloroform (20ml) solution of 3-chlorine third SULPHURYL CHLORIDE (3.35ml), last 20 minutes.After at room temperature stirring 2 hours, in reaction soln, add 5% hydrochloric acid, the mixture chloroform extraction.Organic layer washs with saturated brine, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates is suspended in the Diisopropylamine, filters the collecting precipitation thing, obtain trans-4-{[(3-chloropropyl) alkylsulfonyl] amino }-hexahydrobenzoic acid methyl esters (6.14g).
APCI-MS M/Z：315/317[M+H] +。
(2) with the trans-4-{[(3-chloropropyl that obtains in above-mentioned (1)) alkylsulfonyl] amino }-hexahydrobenzoic acid methyl esters (3.08g) is dissolved in the tetrahydrofuran (THF) (40ml); and under ice-cooled condition, drip tetrahydrofuran (THF) (20ml) solution of potassium tert.-butoxide (1.35g), last 10 minutes.After at room temperature stirring 3.5 hours, under ice-cooled condition, add potassium tert.-butoxide (370mg) again, at room temperature stir the mixture and spend the night.Reaction soln poured in 5% the hydrochloric acid (100ml), water layer is saturated with excessive sodium-chlor, uses chloroform extraction subsequently.The organic layer dried over sodium sulfate, solvent removed by evaporation at reduced pressure.Resulting resistates silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/2, then use ethyl acetate) purifying, obtain trans-4-(1,1-dioxy isothiazolidine-2-yl)-hexahydrobenzoic acid methyl esters (1.42g, APCI-MS M/Z:279[M+NH 4] +) and title compound (0.56g).
ESI-MS M/Z：246[M-H] -。
Reference example 21:2-chloro-N-(5-chloropyridine-2-yl) ethanamide
Figure A20048000194101651
Chloroacetyl chloride (95.5ml) is dissolved in the methylene dichloride (500ml), under ice-cooled condition to methylene dichloride (1000ml) suspension that wherein drips 2-amino-5-chloropyridine (128.6g) and triethylamine (169ml).Reaction soln is warmed to room temperature and stirred 0.5 hour.The concentrating under reduced pressure reaction soln to wherein pouring frozen water into, is used ethyl acetate extraction subsequently.Organic layer washs with saturated brine, dried over sodium sulfate, and use activated carbon treatment.After removing by filter insolubles, concentrating under reduced pressure filtrate, and resulting resistates is suspended in the Di Iso Propyl Ether.Filter the collecting precipitation thing,, obtain title compound (153.4g) with Di Iso Propyl Ether washing and dry.
APCI-MS M/Z：205/207[M+H] +。
Reference example 22:N-(5-chloropyridine-2-yl)-2-hydroxyl acetamide
Figure A20048000194101652
(1) 2-chloro-N-(5-chloropyridine-2-yl) ethanamide (30.68g) that obtains in the reference example 21 is dissolved in N, in the dinethylformamide (500ml), to wherein adding sodium acetate (24.55g).Then mixture was stirred 5 hours down at 60 ℃.With ethyl acetate diluting reaction solution, and water and saturated brine washing successively.With the solution dried over mgso, use activated carbon treatment, and concentrating under reduced pressure filtrate.Resulting resistates is suspended in the normal hexane, and filters and collect crystal.Use the normal hexane washing crystal, and drying obtains 2-[(5-chloropyridine-2-yl) amino]-2-oxoethyl acetic ester (30.58g).
APCI-MS M/Z：229/231[M+H] +。
(2) with the 2-[(5-chloropyridine-2-yl that obtains in above-mentioned (1)) amino]-2-oxoethyl acetic ester (30.36g) is suspended in the methyl alcohol (1200ml), under ice-cooled condition to wherein adding salt of wormwood (22.0g).Reaction soln is warmed to room temperature, stirred 0.5 hour, and concentrating under reduced pressure.In resulting resistates, pour ethyl acetate (1500ml) and frozen water (1000ml) into, use ethyl acetate extraction subsequently.Organic layer washs with saturated brine, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates is suspended in a spot of ethyl acetate, to wherein pouring Di Iso Propyl Ether into.Filter the crystal of collecting precipitation,, obtain title compound (22.85g) with Di Iso Propyl Ether washing and dry.
APCI-MS M/Z：187/189[M+H] +。
Reference example 23:N-(5-chloropyridine-2-yl)-2-[(2-cyanopyridine-3-yl) oxygen base] ethanamide
Figure A20048000194101661
Will (Synthesis 1983 according to document, 316) the 2-cyano-3-hydroxy pyridine (35.0g) of described method acquisition is dissolved in the acetone (800ml), 2-chloro-N-(5-chloropyridine-2-yl) ethanamide (62.6g), salt of wormwood (60.0g) and the sodium iodide (45.8g) that obtain in wherein adding reference example 21.Then mixture heating up was refluxed 2 hours.After cooling, water and ethyl acetate are poured in the reaction mixture, removed by filter insolubles.Separate organic layer then.The water layer ethyl acetate extraction merges organic layer, with saturated brine washing, dried over sodium sulfate.Solvent removed by evaporation at reduced pressure is suspended in resulting resistates in the ether.Filter the collecting precipitation thing, obtain title compound (80.3g).
APCI-MS M/Z：289/291[M+H] +。
Reference example 24:3-amino-N-(5-chloropyridine-2-yl) furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194101671
With N-(5-chloropyridine-2-the yl)-2-[(2-cyanopyridine-3-yl that obtains in the reference example 23) the oxygen base] ethanamide (80.0g) is dissolved in the N,N-dimethylacetamide (700ml), to wherein adding yellow soda ash (35.2g).Then mixture was stirred 10 hours down at 100 ℃.After cooling, with the reaction soln concentrating under reduced pressure, make its volume reduce 1/3.After pouring frozen water into, filter the collecting precipitation thing.Resulting solid suspension in ethyl acetate, and filter is collected.Gains wash successively with chloroform and ether and are dry, obtain title compound (48.5g).
APCI-MS M/Z：289/291[M+H] +。
Reference example 25:4-chlorine apellagrin nitrile
Figure A20048000194101672
(1) at the n-Butyl Lithium/hexane solution that in tetrahydrofuran (THF) (200ml) solution of Diisopropylamine (20.0g), drips 1.6M under the ice-cooled condition.Under identical cooling conditions, stirred the mixture 30 minutes then.Use the dry ice-propanone reaction mixture, to the tetrahydrofuran (THF) that wherein drips 4-chloropyridine (20.4g) (100ml) solution.Restir mixture 20 minutes under identical cooling conditions then.Pour in the broken dry ice resulting reaction soln is disposable, be warmed to room temperature then.Use ice-cooled reaction soln, add sodium hydroxide and make its alkalization, then carry out concentrating under reduced pressure.Resulting resistates is dissolved in the water, and uses washed with dichloromethane.Water layer is with ice-cooled, and uses the concentrated hydrochloric acid acidifying.Filter collecting precipitation thing and dry, obtain 4-chlorine apellagrin hydrochloride (21.4g).
(2) the 4-chlorine apellagrin hydrochloride (500mg) that obtains in above-mentioned (1) is dissolved in the thionyl chloride (6ml), to wherein adding N, dinethylformamide (1).Then with reaction soln reflux 12 hours.After cooling, the concentrating under reduced pressure reaction soln is to dry.Resulting resistates is suspended in the methylene dichloride (10ml), under ice-cooled condition to wherein adding ammonium chloride (152mg) and triethylamine (1.8ml).Under identical cooling conditions, stirred the mixture 2 hours then.In reaction soln, add saturated sodium bicarbonate aqueous solution and sodium-chlor, and use the chloroform extraction mixture.The organic layer dried over sodium sulfate, solvent evaporated under reduced pressure.Through silica gel column chromatography (elutriant: chloroform, then usefulness chloroform/methanol=20/1～10/1) purifying, obtain 4-chloro-nicotinamide (211mg).
APCI-MS M/Z：157/159[M+H] +。
(3) the 4-chloro-nicotinamide (210mg) that obtains in above-mentioned (2) is suspended in the phosphoryl chloride (7ml), mixture was heated 2 hours down at 100 ℃.After cooling, concentrating under reduced pressure reaction soln.In resulting resistates, pouring saturated sodium bicarbonate aqueous solution and chloroform under the ice-cooled condition into.Then mixture is warmed to room temperature, and stirred 1 hour.Separate organic layer, with saturated brine washing, dried over sodium sulfate, solvent removed by evaporation at reduced pressure.Resulting resistates silica gel column chromatography (elutriant: chloroform, use chloroform/methanol=20/1 subsequently) purifying, obtain title compound (115mg).
1H-NMR(CDCl 3，300MHZ)：δ：8.86(1H，d，J＝0.4Hz)，8.71(1H，d，J＝5.4Hz)，7.51(1H，dd，J＝5.4，0.4Hz)。
Reference example 26:N-(5-chloropyridine-2-yl)-2-[(3-cyanopyridine-4-yl) oxygen base] ethanamide
Figure A20048000194101681
N-(5-chloropyridine-2-the yl)-2-hydroxyl acetamide (142mg) that obtains in the reference example 22 is dissolved in N, in the dinethylformamide (3ml), under ice-cooled condition to the sodium hydride oil solution (61mg) that wherein adds 60%.Reaction soln is warmed to room temperature, stirred 15 minutes, use ice-cooledly again, add in the reference example 25 N of the 4-chlorine apellagrin nitrile (105mg) that obtains, dinethylformamide (1ml) solution subsequently.Reaction soln was at room temperature stirred 1 hour, and under ice-cooled condition to wherein pouring water into, use ethyl acetate extraction subsequently.Organic layer water and saturated brine washing, dried over sodium sulfate, solvent removed by evaporation at reduced pressure.Resulting resistates is suspended in normal hexane/Di Iso Propyl Ether, filters and collect and drying, obtain title compound (200mg).
APCI-MS M/Z：289/291[M+H] +。
Reference example 27:3-amino-N-(5-chloropyridine-2-yl) furo [3,2-c] pyridine-2-carboxamide
With N-(5-chloropyridine-2-the yl)-2-[(3-cyanopyridine-4-yl that obtains in the reference example 26) the oxygen base] ethanamide (195mg) is dissolved in the N,N-dimethylacetamide (5ml), to wherein adding yellow soda ash (86mg).Then mixture was stirred 3 hours down at 100 ℃.After cooling, the concentrating under reduced pressure reaction soln, and frozen water poured in the resulting resistates.Filter the collecting precipitation thing, wash with water, with the ether washing, obtain title compound (171mg) then.
APCI-MS M/Z：289/291[M+H] +。
Reference example 28:N-(5-chloropyridine-2-yl)-2-[(4-cyanopyridine-3-yl) oxygen base] ethanamide
(1) the amino iso ethyl nicotinate of 3-(5.55g) is suspended in the water (70ml), to wherein adding the vitriol oil (4.0ml).Use ice-cooled reaction soln, to the water that wherein drips Sodium Nitrite (2.79g) (30ml) solution.Reaction soln was stirred 20 minutes under identical cooling conditions, so stirred 80 minutes down at 90 ℃.Water (100ml) diluting reaction solution, and add saturated sodium bicarbonate aqueous solution solution is adjusted to pH8-9, chloroform extraction used subsequently.Organic layer dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.(elutriant: n-hexane/ethyl acetate=5/1) purifying obtains 3-hydroxy-isonicotinic acid ethyl ester (2.64g) to resulting resistates with silica gel column chromatography.
APCI-MS M/Z：168[M+H] +。
(2) the 3-hydroxy-isonicotinic acid ethyl ester (1.60g) that obtains in above-mentioned (1) is dissolved in the ethanol (30ml), under ice-cooled condition, steeps to wherein rousing ammonia.In reaction soln, add tetrahydrofuran (THF) (50ml), again drum ammonia bubble in mixture.Reaction soln is warmed to room temperature, and stirred 3 hours.Stop drum ammonia bubble, mixture was at room temperature stirred 2.5 days.The concentrating under reduced pressure reaction soln obtains 3-hydroxyl Isonicotinamide (1.35g) to dry.
ESI-MS M/Z：137[M-H] -。
(3) pyridine (1.20ml) is added drop-wise in methylene dichloride (30ml) solution of trifluoroacetic anhydride (3.10g), and methylene dichloride (10ml) suspension of 3-hydroxyl Isonicotinamide (683mg) of obtaining in above-mentioned (2) is divided into aliquot under ice-cooled condition, adds wherein.Reaction soln is warmed to room temperature, stirred 13 hours, then to wherein adding entry and saturated sodium bicarbonate aqueous solution.Separate water layer, and be evaporated to driedly, obtain 3-hydroxy-isonicotinic acid nitrile crude product.Then, resulting crude product is suspended in the acetone (50ml), 2-chloro-N-(5-chloropyridine-2-yl) ethanamide (1.08g), cesium carbonate (3.03g) and the sodium iodide (0.78g) that obtain in wherein adding reference example 21 reflux mixture heating up 19 hours.After cooling, water, tetrahydrofuran (THF) and ethyl acetate are poured in the mixture, removed by filter insolubles.Separate organic layer, use dried over mgso, solvent removed by evaporation at reduced pressure.Resulting resistates obtains title compound (87mg) with silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/1 then is 1/2) purifying.
APCI-MS M/Z：289/291[M+H] +。
Reference example 29:3-amino-N-(5-chloropyridine-2-yl) furo [2,3-c] pyridine-2-carboxamide
With N-(5-chloropyridine-2-the yl)-2-[(4-cyanopyridine-3-yl that obtains in the reference example 28) the oxygen base] ethanamide is dissolved in the N,N-dimethylacetamide (5ml), to wherein adding yellow soda ash (39mg).Under 100 ℃, stirred the mixture 3 hours then.After cooling, dilute with water reaction soln.Filter the collecting precipitation thing, wash with water, drying obtains title compound (47mg).
APCI-MS M/Z：289/291[M+H] +。
Reference example 30:N-(5-chloropyridine-2-yl)-2-[(3-cyanopyridine-2-yl) oxygen base] ethanamide
N-(5-chloropyridine-2-the yl)-2-hydroxyl acetamide (187mg) that obtains in the reference example 22 is dissolved in N, in the dinethylformamide (3ml), to the sodium hydride oil solution (80mg) that wherein adds 60%.Reaction soln was stirred 15 minutes, to wherein adding 2-chlorine apellagrin nitrile (139mg).At room temperature stirring reaction solution is 1 hour, ice-cooled following to wherein adding saturated aqueous ammonium chloride and water successively.Filter the collecting precipitation thing, water and Di Iso Propyl Ether washing and dry obtains title compound (212mg) successively.
APCI-MS M/Z：289/291[M+H] +。
Reference example 31:3-amino-N-(5-chloropyridine-2-yl) furo [2,3-b]-pyridine-2-carboxamide
Figure A20048000194101711
With N-(5-chloropyridine-2-the yl)-2-[(3-cyanopyridine-2-yl that obtains in the reference example 30) the oxygen base] ethanamide is dissolved in the N,N-dimethylacetamide (3ml), to wherein adding yellow soda ash (92mg).Then mixture is stirred down at 100 ℃ and spend the night.In mixture, add yellow soda ash (90mg) again, once more mixture is stirred down at 100 ℃ and spend the night.After cooling, in reaction soln, pour frozen water into.Filter the collecting precipitation thing, it is dissolved in the chloroform/methanol, and uses dried over sodium sulfate.Solvent removed by evaporation at reduced pressure is suspended in resulting resistates in the n-hexane/ethyl acetate.Filter the collecting precipitation thing, obtain title compound (111mg).
APCI-MS M/Z：289/291[M+H] +。
Reference example 32:3-chloropyrazine-2-nitrile
Pyrazine-2-nitrile (26.36g) is dissolved in toluene (187ml)/N, dinethylformamide (19ml), and under ice-cooled condition to wherein dripping SULPHURYL CHLORIDE (135g).After adding, reaction soln progressively is warmed to room temperature, and stirs and spend the night.The separation of methylbenzene layer, remaining red oil extracted with diethyl ether.Merge organic layer,,, add saturated sodium bicarbonate aqueous solution and neutralize after wherein pouring frozen water into ice-cooled.Separate organic layer, the water layer extracted with diethyl ether.Merge organic layer, wash dried over sodium sulfate, and solvent removed by evaporation at reduced pressure with water.(elutriant: n-hexane/ethyl acetate=4/1) purifying obtains title compound (16.58g) to resulting resistates with silica gel column chromatography.
1H-NMR(CDCl 3，300MHZ)：δ：8.66(1H，d，J＝2.4Hz)，8.61(1H，d，J＝2.4Hz)。
Reference example 33:N-(5-chloropyridine-2-yl)-2-[(3-cyanopyrazine-2-yl) oxygen base] ethanamide
N-(5-chloropyridine-2-the yl)-2-hydroxyl acetamide (1.34g) that obtains in the reference example 22 is dissolved in N, in the dinethylformamide (15ml), to the sodium hydride oil solution (574mg) that wherein adds 60%.At room temperature stirring reaction solution is 15 minutes, uses ice-cooledly once more, and adds the N of the 3-chloropyrazine-2-nitrile (1.0g) that obtains in the reference example 32, dinethylformamide (5ml) solution.Reaction soln was at room temperature stirred 1 hour, under ice-cooled condition,, use ethyl acetate extraction subsequently to wherein pouring water into.Organic layer water and saturated brine washing, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates is suspended in normal hexane-Di Iso Propyl Ether.Filter collecting precipitation thing and dry, obtain title compound (1.92g).
APCI-MS M/Z：290/292[M+H] +。
Reference example 34:7-amino-N-(5-chloropyridine-2-yl) furo [2,3-b] pyrazine-6-methane amide
With N-(5-chloropyridine-2-the yl)-2-[(3-cyanopyrazine-2-yl that obtains in the reference example 33) the oxygen base] ethanamide (1.90g) is dissolved in N, in the N-N,N-DIMETHYLACETAMIDE (20ml), to wherein adding yellow soda ash (834mg), under 100 ℃, stirred the mixture 3 days.After cooling, the concentrating under reduced pressure reaction soln is poured water in the resistates into.Filter the collecting precipitation thing,, obtain title compound (0.38g) with ether washing and dry.
APCI-MS M/Z：290/292[M+H] +。
Reference example 35:5-pyridone-2-carboxylate methyl ester 1-oxide compound
In methylene dichloride (75ml) suspension of 5-pyridone-2-carboxylate methyl ester (5.30g), add under the ice-cooled condition metachloroperbenzoic acid (＞65%, 11.0g), at room temperature stirred the mixture 5 hours.The concentrating under reduced pressure reaction soln.Resistates is suspended in the ethyl acetate, and the filtration collection obtains title compound (4.62g).The concentrating under reduced pressure mother liquor, resulting resistates silica gel column chromatography (elutriant: chloroform～methyl alcohol/chloroform=1/5) purifying.Resulting solid suspension in ethylacetate/ether, and filter is collected and to be obtained title compound (0.68g).
APCI-MS M/Z：170[M+H] +。
Reference example 36:6-cyano group-5-pyridone-2-carboxylate methyl ester
Figure A20048000194101732
5-pyridone-2-carboxylate methyl ester 1-the oxide compound (5.18g), sodium cyanide (4.50g) and the triethylamine (29.9ml) that obtain in the reference example 35 are added to N, in the dinethylformamide (55ml), to wherein adding chloro three silicomethanes (19.4ml), last 20 minutes.Mixture was stirred 28 hours down at 80 ℃.Reaction soln is cooled to room temperature, removes by filter insolubles, and concentrating under reduced pressure filtrate.In resistates, add methyl alcohol (150ml), under room temperature, stirred the mixture 30 minutes, and solvent removed by evaporation at reduced pressure.Resistates silica gel column chromatography (elutriant: chloroform～methyl alcohol/chloroform=1/5) purifying.Resulting solid suspension in ether, is filtered collection and obtains title compound (4.66g).
ESI-MS M/Z：177[M-H] -。
Reference example 37-43
Corresponding precursor compound is handled with the mode that is similar to reference example 35, obtained following compound.
Table 74
Figure A20048000194101751
Reference example 44-50
Corresponding precursor compound is handled with the mode that is similar to reference example 36, obtained following compound.
Table 75
Figure A20048000194101761
Reference example 51-58
Corresponding precursor compound is handled with the mode that is similar to reference example 23, obtained following compound.
Table 76
Table 77
Figure A20048000194101781
Reference example 59-66
Corresponding precursor compound is handled with the mode that is similar to reference example 24, obtained following compound.
Table 78
Figure A20048000194101791
Reference example 67:3-amino-2-{[(5-chloropyridine-2-yl) amino]-carbonyl } furo [3,2-b] pyridine-5-carboxylic acid
Figure A20048000194101801
With the 3-amino-2-{[(5-chloropyridine-2-yl that obtains in the reference example 63) amino] carbonyl } furo [3,2-b] pyridine-5-carboxylate methyl ester (800mg) was suspended in tetrahydrofuran (THF)/methyl alcohol (3: 1,40ml), to the aqueous sodium hydroxide solution that wherein adds 1N (11.5ml).At room temperature stirred the mixture then 2 days.With 1N hydrochloric acid (11.5ml) neutralization reaction solution, and dilute with water.Filter the collecting precipitation solid, drying obtains title compound (615mg).
ESI-MS M/Z：331/333[M-H] -。
Reference example 68
Corresponding precursor compound is handled with the mode that is similar to reference example 67, obtained following compound.
Table 79
Figure A20048000194101802
Reference example 69:3-amino-N 2-(5-chloropyridine-2-yl)-N 5, N 5-dimethyl furan is [3,2-b] pyridine-2 also, the 5-diformamide
Figure A20048000194101803
With the 3-amino-2-{[(5-chloropyridine-2-yl that obtains in the reference example 67) amino]-carbonyl } furo [3,2-b] pyridine-5-carboxylic acid (605mg) is suspended in N, in the dinethylformamide (10ml), to wherein adding dimethylamine hydrochloride (297mg), I-hydroxybenzotriazole (492mg), 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (698mg) and triethylamine (634 μ l) successively.At room temperature stirred the mixture then 24 hours.The concentrating under reduced pressure reaction soln.Pour saturated sodium bicarbonate aqueous solution and water into to resulting resistates.Filter the collecting precipitation solid, water and ether washing and dry obtain title compound (621mg).
APCI-MS M/Z：360/362[M+H] +。
Reference example 70
Corresponding precursor compound is handled with the mode that is similar to reference example 69, obtained following compound.
Table 80
Reference example 71: trans-4-[4-(tertbutyloxycarbonyl)-2-oxo piperazine-1-yl] hexahydrobenzoic acid
(1) trans-4-aminocyclohexane carboxylate methyl ester hydrochloride (1.22g) that obtains in the reference example 2 (1) is suspended in the methylene dichloride (10ml), to wherein adding triethylamine (1.76ml) and mixture being stirred several minutes.Under ice-cooled condition, add methylene dichloride (5ml) solution and the sodium triacetoxy borohydride (1.46g) of (2-oxoethyl) t-butyl carbamate (1.00g) successively, reaction soln is warmed to room temperature, and stirred 15 hours.Saturated sodium bicarbonate aqueous solution is poured in the reaction soln, and used the chloroform extraction mixture.Organic layer dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.With the part (1.71g) of resulting resistates (2.33g) with silica gel column chromatography (elutriant: chloroform/methanol=10/1) purifying obtains trans-4-({ 2-[(tertbutyloxycarbonyl) amino] ethyl } amino)-hexahydrobenzoic acid methyl esters (793mg).
APCI-MS M/Z：301[M+H] +。
(2) with trans-4-of obtaining in the reference example 71 (1) ({ 2-[(tertbutyloxycarbonyl) amino] ethyl amino)-hexahydrobenzoic acid methyl esters (785mg) is dissolved in the chloroform (8ml), under ice-cooled condition to wherein adding triethylamine (1.82ml) and chloroacetyl chloride (249 μ l).At room temperature stirred the mixture then 2 hours.Use ice-cooled reaction soln again, to wherein replenishing chloroacetyl chloride (62 μ l).Mixture was at room temperature stirred 1 hour.In reaction soln, pour saturated sodium bicarbonate aqueous solution into, and use the chloroform extraction mixture.Organic layer water and saturated brine wash successively, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates obtains trans-4-[{2-[(tertbutyloxycarbonyl with silica gel column chromatography (elutriant: n-hexane/ethyl acetate=2/1 is 1/1 subsequently) purifying) amino] ethyl }-(chloracetyl) amino]-hexahydrobenzoic acid methyl esters (568mg).
APCI-MS M/Z：377/379[M+H] +。
(3) with the trans-4-[{2-[(tertbutyloxycarbonyls that obtain in the reference example 71 (2)) amino] ethyl }-(chloracetyl) amino]-hexahydrobenzoic acid methyl esters (560mg) is dissolved in N; in the N-N,N-DIMETHYLACETAMIDE (5ml), under ice-cooled condition to the sodium hydride oil solution (119mg) that wherein adds 60%.Under identical cooling conditions, reaction soln was stirred 0.5 hour then.Under ice-cooled condition, successively saturated aqueous ammonium chloride and water are poured in the reaction soln, and used the ethyl acetate extraction mixture.Organic layer water and saturated brine wash successively, use dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates with silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/1) purifying, obtain 4-[trans-4-(methoxycarbonyl) cyclohexyl]-3-oxo piperazine-1-carboxylic acid tert-butyl ester (302mg).
APCI-MS M/Z：341[M+H] +。
(4) with the 4-[that obtain in the reference example 71 (3) trans-4-(methoxycarbonyl) cyclohexyl]-3-oxo piperazine-1-carboxylic acid tert-butyl ester (385mg) is dissolved in the methyl alcohol (8ml), under ice-cooled condition to wherein adding 1N aqueous sodium hydroxide solution (3.4ml).Reaction soln is at room temperature stirred 20 hours, and concentrating under reduced pressure.In resistates, pour water and chloroform into, add 2N hydrochloric acid and come the acidifying water layer.Separate organic layer, with saturated brine washing, dried over sodium sulfate.Solvent removed by evaporation at reduced pressure obtains title compound (375mg).
ESI-MS M/Z：325[M-H] -。
Reference example 72:2-[(6-bromo-2-cyanopyridine-3-yl) oxygen base]-N-(5-chloropyridine-2-yl) ethanamide
Figure A20048000194101831
(1) 2-cyano-3-hydroxy pyridine (3.00g) is dissolved in acetonitrile/water (5: 1,90ml) in, under ice-cooled condition, N-bromine succinimide (5.34g) is divided into aliquot and adds wherein.Under identical cooling conditions, stirred the mixture 2 hours then.Reaction soln dilutes with ethyl acetate, and water and saturated brine wash successively, and uses dried over sodium sulfate.Solvent removed by evaporation at reduced pressure obtains 6-bromo-3-pyridone-2-nitrile crude product (6.26g).
ESI-MS M/Z：197/199[M-H] -。
(2) the 6-bromo-3-pyridone-2-nitrile (6.20g) that obtains in the reference example 72 (1) is handled with the mode that is similar to reference example 23, obtained title compound (4.36g).
APCI-MS M/Z：367/369[M+H] +。
Reference example 73:3-amino-5-bromo-N-(5-chloropyridine-2-yl)-furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194101832
With the 2-[(6-bromo-2-cyanopyridine-3-yl that obtains in the reference example 72) the oxygen base]-N-(5-chloropyridine-2-yl) ethanamide (4.00g) handles with the mode that is similar to reference example 24, obtains title compound (2.96g).
APCI-MS M/Z：367/369[M+H] +。
Reference example 74:2-chloro-N-(4-chloro-phenyl-) ethanamide
5-chloroaniline (7.03g) is handled with the mode that is similar to reference example 21, obtained title compound (10.18g).
APCI-MS M/Z：204/206[M+H] +。
Reference example 75:N-(4-chloro-phenyl-)-2-[(2-cyanopyridine-3-yl) oxygen base] ethanamide
Figure A20048000194101842
2-chloro-N-(4-chloro-phenyl-) ethanamide that obtains in 2-cyano-3-hydroxy pyridine (2.00g) and the reference example 74 is handled with the mode that is similar to reference example 23, obtained title compound (4.58g).
APCI-MS M/Z：288/290[M+H] +。
Reference example 76:3-amino-N-(4-chloro-phenyl-) furo [3,2-b] pyridine-2-carboxamide
Figure A20048000194101843
With N-(4-the chloro-phenyl-)-2-[(2-cyanopyridine-3-yl that obtains in the reference example 75) the oxygen base] ethanamide handles with the mode that is similar to reference example 24, obtains title compound (2.98g).
APCI-MS M/Z：288/290[M+H] +。
Reference example 77:[(2-cyanopyridine-3-yl) oxygen base] methyl acetate
2-cyano-3-hydroxy pyridine (5.00g) is dissolved in the acetone (50ml), to wherein adding monobromo-acetic acid methyl esters (7.0g) and salt of wormwood (6.3g).Mixture heating up was refluxed 1.5 hours.After cooling, in reaction soln, pour frozen water into, and use ethyl acetate extraction.Organic layer washs with saturated brine, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates is suspended in ether/normal hexane, and solid collected by filtration obtains title compound (7.91g).
APCI-MS M/Z：193[M+H] +。
Amino furo [3,2-b] the pyridine-2-carboxylic acids methyl esters of reference example 78:3-
[(2-cyanopyridine-3-yl) oxygen base] methyl acetate (4.00g) that obtains in the reference example 77 is dissolved in the tetrahydrofuran (THF) (100ml), under ice-cooled condition, 60% sodium hydride oil solution (1.53g) is divided into aliquot and adds.Reaction soln is warmed to room temperature, and stirred 1 hour.Under ice-cooled condition, reaction soln is poured in ammonium chloride/aqueous citric acid solution, used ethyl acetate extraction subsequently.Organic layer washs with saturated brine, dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resulting resistates is suspended in the normal hexane, and solid collected by filtration obtains title compound (2.96g).
APCI-MS M/Z：193[M+H] +。
Reference example 79:3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxylic acids methyl esters
Trans-4-(the 3-oxo morpholine-4-yl) hexahydrobenzoic acid (3.55g) that obtains in the reference example 4 is dissolved in the thionyl chloride (20ml).At room temperature stirred the mixture then 15 hours.The concentrating under reduced pressure reaction soln, resistates carries out component distillation with toluene and is dissolved in the chloroform (25ml).Under ice-cooled condition,, reaction soln is warmed to room temperature, and stirred 5 hours amino furo [3,2-b] pyridine-2-carboxylic acids methyl esters (2.00g) of the 3-that obtains in the reference example 78 and pyridine (1.68ml) order adding according to this.Under ice-cooled condition, saturated sodium bicarbonate aqueous solution is poured in the reaction soln, and used the chloroform extraction mixture.Organic layer water and saturated brine wash successively, use dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resistates NH-silica gel column chromatography (elutriant: ethyl acetate, then with ethyl acetate/methanol=5/1) purifying.Resulting solid suspension in ether/normal hexane, is filtered collection and obtains title compound (3.54g).
APCI-MS M/Z：402[M+H] +。
Reference example 80: trans-the 4-[(dimethylamino) hexahydrobenzoic acid carbonyl)]
Figure A20048000194101861
(1) trans-4-(methoxycarbonyl) hexahydrobenzoic acid (20.0g) that obtains in the reference example 1 (2) is dissolved in the chloroform (200ml), under ice-cooled condition to wherein adding dimethylamine hydrochloride (10.5g), 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (24.7g) and triethylamine (26.0g).At room temperature stirred the mixture then 17 hours.Frozen water is poured in the reaction soln, and used the chloroform extraction mixture.Organic layer washs with 10% hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated brine successively, and uses dried over sodium sulfate.Solvent removed by evaporation at reduced pressure, resulting resistates silica gel column chromatography (elutriant: chloroform, then with chloroform/methanol=20/1) purifying, and obtain trans-4-[(dimethylamino) carbonyl]-hexahydrobenzoic acid methyl esters (20.1g).
APCI-MS M/Z：214[M+H] +。
(2) with the trans-4-[(dimethylaminos that obtain in the reference example 80 (1)) carbonyl]-hexahydrobenzoic acid methyl esters (20.0g) is dissolved in the methyl alcohol (100ml), to the water that wherein adds sodium hydroxide (7.50g) (40ml) solution.At room temperature stirred the mixture then 18 hours.The concentrating under reduced pressure reaction soln, resistates dilutes with frozen water, and washs with ether.Resulting water layer 10% hcl acidifying is used twice of chloroform extraction.Organic layer washs with saturated brine, and uses dried over sodium sulfate.The concentrating under reduced pressure solvent.Resulting resistates is suspended in the normal hexane, filters collection and obtain title compound (15.7g).
ESI-MS M/Z：198[M-H] -。
Reference example 81: trans-4-(tetramethyleneimine-1-base carbonyl) hexahydrobenzoic acid
(1) trans-4-(methoxycarbonyl) hexahydrobenzoic acid (20.0g) that obtains in the reference example 1 (2) is dissolved in the chloroform (200ml), under ice-cooled condition to wherein adding tetramethyleneimine (9.2g), 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (24.7g) and triethylamine (13.6g).At room temperature stirred the mixture then 17 hours.Frozen water is poured in the reaction soln, and used the chloroform extraction mixture.Organic layer with 10% hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated brine washing, is used dried over sodium sulfate successively.The concentrating under reduced pressure solvent.Resulting resistates silica gel column chromatography (elutriant: chloroform, use chloroform/methanol=20/1 subsequently) purifying, obtain trans-4-(tetramethyleneimine-1-base carbonyl)-hexahydrobenzoic acid methyl esters (11.8g).
APCI-MS M/Z：240[M+H] +。
(2) trans-4-(tetramethyleneimine-1-base the carbonyl)-hexahydrobenzoic acid methyl esters (11.7g) that obtains in the reference example 81 (1) is dissolved in the methyl alcohol (50ml), to the water that wherein adds sodium hydroxide (3.95g) (20ml) solution.At room temperature stirred the mixture then 18 hours.The concentrating under reduced pressure reaction soln.Resistates dilutes with frozen water, and washs with ether.Resulting water layer is with 10% hcl acidifying, and with twice of chloroform extraction.Organic layer washs with saturated brine, and uses dried over sodium sulfate.The concentrating under reduced pressure solvent.Resulting resistates is suspended in the normal hexane, filters collection and obtain title compound (10.1g).
ESI-MS M/Z：224[M-H] -。
Reference example 82: trans-4-(morpholine-4-base carbonyl) hexahydrobenzoic acid
Figure A20048000194101872
(1) trans-4-(methoxycarbonyl) hexahydrobenzoic acid (800mg) that obtains in the reference example 1 (2) is dissolved in the chloroform (30ml), under ice-cooled condition to wherein adding morpholine (560mg), 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (1.24g) and triethylamine (650mg).At room temperature stirred the mixture then 19 hours.Frozen water is poured in the reaction soln, and used the chloroform extraction mixture.Organic layer with 10% hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated brine washing, is used dried over sodium sulfate successively.The concentrating under reduced pressure solvent.Resulting resistates silica gel column chromatography (elutriant: chloroform, use chloroform/methanol=30/1 subsequently) purifying, obtain trans-4-(morpholine-4-base carbonyl)-hexahydrobenzoic acid methyl esters (897mg).
APCI-MS M/Z：256[M+H] +。
(2) trans-4-(morpholine-4-base the carbonyl)-hexahydrobenzoic acid methyl esters (860mg) that obtains in the reference example 82 (1) is dissolved in the methyl alcohol (40ml), to wherein adding 4N aqueous sodium hydroxide solution (1.68ml).At room temperature stirred the mixture then 18 hours.The concentrating under reduced pressure reaction soln.Resistates dilutes with frozen water, the hydrochloric acid neutralization with 10%, and use chloroform extraction.Organic layer dried over sodium sulfate, concentrating under reduced pressure solvent obtain title compound (638mg).
ESI-MS M/Z：240[M-H] -。
Reference example 83: trans-4-{[[2-(dimethylamino) ethyl] (methyl)-amino] carbonyl } hexahydrobenzoic acid
Figure A20048000194101881
(1) trans-4-(methoxycarbonyl) hexahydrobenzoic acid (8.84g) that obtains in the reference example 1 (2) is dissolved in the chloroform (100ml), under ice-cooled condition to wherein adding I-hydroxybenzotriazole (7.14g), 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (10.00g) and N, N, N '-trimethylammonium quadrol (5.33g).At room temperature stirred the mixture then 4 hours.Saturated sodium bicarbonate aqueous solution is poured in the reaction soln, and used the chloroform extraction mixture.Organic layer washs with saturated brine, uses dried over sodium sulfate.The concentrating under reduced pressure solvent.Resulting resistates silica gel column chromatography (elutriant: chloroform/methanol/28% ammoniacal liquor=200/10/1) purifying obtains trans-4-{[[2-(dimethylamino) ethyl] (methyl) amino] carbonyl }-hexahydrobenzoic acid methyl esters (11.98g).
APCI-MS M/Z：271[M+H] +。
(2) with trans-4-{[[2-(dimethylamino) ethyls that obtain in the reference example 83 (1)] (methyl) amino] carbonyl }-hexahydrobenzoic acid methyl esters (6.32g) is dissolved in the methyl alcohol (20ml), to the aqueous sodium hydroxide solution that wherein adds 1N (25ml).At room temperature stirred the mixture 3 hours.The hydrochloric acid (25ml) that in reaction soln, adds 1N, and concentrating under reduced pressure reaction soln.Lyophilized residue obtains the title compound crude product (6.71g) of mole nacls such as comprising.
APCI-MS M/Z：257[M+H] +。
Reference example 84:6-morpholine-4-base-6-oxo caproic acid
Figure A20048000194101891
(1) monomethyl adipate (3.20g) is dissolved in the chloroform (70ml), under ice-cooled condition to wherein adding morpholine (2.61g), 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (5.75g) and triethylamine (3.04g).At room temperature stirred the mixture then 19 hours.Frozen water is added in the reaction soln, and use the chloroform extraction mixture.Organic layer with 10% hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated brine washing, is used dried over sodium sulfate successively.Solvent removed by evaporation at reduced pressure obtains 6-morpholine-4-base-6-oxo methyl caproate (4.63g).
APCI-MS M/Z：230[M+H] +。
(2) the 6-morpholine-4-base-6-oxo methyl caproate (4.60g) that obtains in the reference example 84 (1) is dissolved in the methyl alcohol (20ml), to the water that wherein adds sodium hydroxide (1.61g) (8ml) solution.At room temperature stirred the mixture 19 hours.The concentrating under reduced pressure reaction soln, resistates neutralizes with 2N hydrochloric acid.The concentrating under reduced pressure resistates, and use chloroform extraction.The organic layer dried over sodium sulfate, the concentrating under reduced pressure solvent obtains title compound (4.11g).
ESI-MS M/Z：214[M-H] -。
Reference example 85:5-morpholine-4-base-5-oxopentanoic acid ester
Pyroglutaric acid (1.14g) is dissolved in the tetrahydrofuran (THF) (20ml), to wherein adding morpholine (0.87g).At room temperature stirred the mixture then 19 hours.The concentrating under reduced pressure reaction soln, resistates dilutes with chloroform, and with 10% salt acid elution.The organic layer dried over sodium sulfate, solvent removed by evaporation at reduced pressure obtains title compound (1.05g).
ESI-MS M/Z：200[M-H] -。
Reference example 86:N-(5-chloropyridine-2-yl)-2-[(2-bromo-3-cyanopyridine-4-yl) oxygen base] ethanamide
Figure A20048000194101901
(1) with 2-bromo-3-cyano group-4 (1H) pyridone (reference: M.Mittelback etc., Arch.Pharm., 1985,318,481-486) (837mg) is suspended in the acetone (30ml), 2-chloro-N-(5-chloropyridine-2-yl) ethanamide (1.22g) and the sodium iodide (900mg) that obtain in wherein adding salt of wormwood (853mg), reference example 21.Mixture heating up was refluxed 2 hours 20 minutes.Further adding 2-chloro-N-(5-chloropyridine-2-yl) ethanamide (221mg) that obtains in salt of wormwood (150mg), the reference example 21 and sodium iodide (162mg) afterwards, again with reaction mixture reflux 45 minutes.Allow the reaction soln cool to room temperature, and be poured in the water.Filter the collecting precipitation solid.Resulting solid is dissolved in the tetrahydrofuran (THF), with dried over sodium sulfate and solvent removed by evaporation at reduced pressure.With resulting resistates silica gel column chromatography (elutriant: chloroform/methanol=50/1 is 30/1 subsequently, uses 9/1 again) purifying, and be suspended in chloroform/Di Iso Propyl Ether.Filter the collecting precipitation thing, obtain title compound (669mg).
APCI-MS M/Z：367/369[M+H] +。
Reference example 87:3-amino-4-bromo-N-(5-chloropyridine-2-yl) furo [3,2-c] pyridine-2-carboxamide
With N-(5-chloropyridine-2-the yl)-2-[(2-bromo-3-cyanopyridine-4-yl that obtains in the reference example 86) the oxygen base] ethanamide (429mg) handles with the mode that is similar to reference example 24, obtains title compound (260mg).
APCI-MS M/Z：367/369[M+H] +。
Reference example 88:3-amino-4-methoxyl group-N-(5-chloropyridine-2-yl) furo [3,2-c] pyridine-2-carboxamide
Figure A20048000194101911
With 3-amino-4-bromo-N-(5-chloropyridine-2-yl) furo [3 that obtains in the reference example 87,2-c] pyridine-2-carboxamide (125mg) is suspended in N, in the dinethylformamide (2ml), under ice-cooled condition to the sodium hydride oil solution (69mg) that wherein adds methyl alcohol (200 μ l) and 60%.At room temperature stirred the mixture 3.5 hours.In reaction soln, add aqueous citric acid solution, filter the solid of collecting precipitation, obtain title compound (82mg).
APCI-MS M/Z：319/321[M+H] +。
Reference example 89:3-amino-N-(5-chloropyridine-2-yl)-4-(2-methoxyethoxy) furo [3,2-c] pyridine-2-carboxamide
Figure A20048000194101912
With 3-amino-4-bromo-N-(5-chloropyridine-2-yl) furo [3 that obtains in the reference example 87,2-c] pyridine-2-carboxamide (508mg) is suspended in N, in the dinethylformamide (10ml), under ice-cooled condition to the sodium hydride oil solution (280mg) that wherein adds 2-methoxyethanol (2ml) and 60%.At room temperature stirred the mixture 20 hours, and reaction soln is added in the aqueous citric acid solution.Filter the solid of collecting precipitation, water and washing with alcohol, drying under reduced pressure obtains title compound (377mg).
APCI-MS M/Z：363/365[M+H] +。
Reference example 90:3-amino-N-(5-chloropyridine-2-yl)-4-methyl-furo [3,2-c] pyridine-2-carboxamide
With 3-amino-4-bromo-N-(5-chloropyridine-2-yl) furo [3 that obtains in the reference example 87,2-c] pyridine-2-carboxamide (1.09g) be suspended in 10% 1, in the 4-diox aqueous solution (30ml), at room temperature to wherein adding trimethyl-boron oxygen cycloalkanes (0.57ml) and salt of wormwood (1.67g).With the reaction soln degassing and use argon replaces, to wherein adding four (triphenyl phosphine) palladium (0) (416mg).With the further degassing and use argon replaces of mixture, 110 ℃ of stirrings 21 hours down.After adding entry, with the chloroform extraction reaction soln that comprises small amount of methanol.Organic layer dried over sodium sulfate, and solvent removed by evaporation at reduced pressure.Resistates NH-silica gel column chromatography (elutriant: n-hexane/ethyl acetate=3/1, use 1/1 subsequently) purifying, obtain title compound (775mg).
APCI-MS M/Z：303/305[M+H] +。
Reference example 91:3-amino-N-(5-chloropyridine-2-yl)-4-cyano group furo [3,2-c] pyridine-2-carboxamide
Figure A20048000194101922
To 3-amino-4-bromo-N-(5-chloropyridine-2-yl) furo [3 that obtains in the reference example 87,2-c] pyridine-2-carboxamide (103mg) and zinc cyanide (24mg) be at N, suspension in the dinethylformamide (6ml) outgases and uses argon replaces, to wherein adding four (triphenyl phosphine) palladium (0) (23mg).Mixture outgased once more and use argon replaces, stirred 4 days down at 80 ℃.In reaction soln, add entry and chloroform, remove by filter insolubles.Separate organic layer and use dried over sodium sulfate.And solvent removed by evaporation at reduced pressure.The resistates silica gel column chromatography (elutriant: n-hexane/ethyl acetate=70/30, use 40/60 subsequently) purifying, obtain title compound (21mg).
APCI-MS M/Z：314/316[M+H] +。
Reference example 92:3-(benzyloxy)-6-bromopyridine-2-nitrile
Figure A20048000194101931
The 6-bromo-3-pyridone-2-nitrile (53.8g) that obtains in the reference example 72 (1) is dissolved in the acetone (550ml), to wherein adding bromotoluene (35.6ml) and salt of wormwood (43.1g).Then mixture heating up was refluxed 4 hours.After cooling, (600ml) is added in the reaction soln with water, and uses the ethyl acetate extraction mixture.Water layer with ethyl acetate extraction once and previous organic layer merge.Solution is washed dried over sodium sulfate with saturated brine.Solvent removed by evaporation at reduced pressure, and the resistates silica gel column chromatography (elutriant: n-hexane/ethyl acetate=5/1, use 3/1 subsequently) purifying.Resulting resistates is suspended in ether/normal hexane, and solid collected by filtration obtains title compound (24.1g).
APCI-MS M/Z：289/291[M+H] +。
Reference example 93:3-(benzyloxy)-6-(dimethylamino) pyridine-2-nitrile
3-(the benzyloxy)-6-bromopyridine-2-nitrile (2.50g) that obtains in the reference example 92 is added in the toluene (25ml), (158mg) and 2-(dicyclohexyl phosphino-) biphenyl (243mg) to the dimethylamine/tetrahydrofuran solution that wherein adds 2mol/l (8.65ml), Tripotassium phosphate (2.75g), three (dibenzalacetones), two palladiums (0).In sealed tube, reaction soln was heated 24 hours down at 80 ℃, to the dimethylamine-tetrahydrofuran solution that wherein adds 2mol/l (8.65ml), Tripotassium phosphate (1.38g), three (dibenzalacetones), two palladiums (0) (79mg) and 2-(dicyclohexyl phosphino-) biphenyl (122mg), then in sealed tube again 80 ℃ of heating 24 hours down.After cooling, water is poured in the reaction soln, and used the ethyl acetate extraction mixture.Organic layer washs with saturated brine, and uses dried over sodium sulfate.Solvent evaporated under reduced pressure, (elutriant: normal hexane/chloroform=1/2) purifying obtains title compound (1.29g) to resistates with silica gel column chromatography.
APCI-MS M/Z：254[M+H] +。
Reference example 94:3-(benzyloxy)-6-(methylamino-) pyridine-2-nitrile
3-(the benzyloxy)-6-bromopyridine-2-nitrile (2.00g) of acquisition in the reference example 92 and methylamine/tetrahydrofuran solution (26.0ml) of 2mol/l are handled with the mode that is similar to reference example 93, obtained title compound (0.34g).
APCI-MS M/Z：240[M+H] +。
Reference example 95:[5-(benzyloxy)-6-cyanopyridine-2-yl] the methyl carbamic acid tert-butyl ester
Figure A20048000194101942
3-(benzyloxy)-6-(methylamino-) pyridine-2-nitrile (335mg) that obtains in the reference example 94 is dissolved in the chloroform (7ml), under ice-cooled condition to wherein adding tert-Butyl dicarbonate (321mg) and 4-dimethylaminopyridine (34mg).Mixture was at room temperature stirred 2 hours, then stirred 2 hours down at 50 ℃.Tert-Butyl dicarbonate (321mg) and 4-dimethylaminopyridine (17mg) are added in the reaction soln, and mixture heating up was refluxed 5 hours.In addition, in reaction mixture, add tert-Butyl dicarbonate (642mg) and 4-dimethylaminopyridine (137mg), mixture was stirred 15 hours down at 60 ℃.After adding tert-Butyl dicarbonate (920mg) and 4-dimethylaminopyridine (171mg), mixture heating up was refluxed 10 hours.Allow reaction soln cool off,, then use chloroform extraction to wherein pouring water into.Organic layer washs with saturated brine, dried over sodium sulfate.Solvent removed by evaporation at reduced pressure.Resistates obtains title compound (156mg) with silica gel column chromatography (elutriant: n-hexane/ethyl acetate=5/1 then is 2/1) purifying.
APCI-MS M/Z：340[M+H] +。
Reference example 96:3-(benzyloxy)-6-morpholine-4-yl pyridines-2-nitrile
Figure A20048000194101951
3-(the benzyloxy)-6-bromopyridine-2-nitrile (1.00g) that obtains in the reference example 92 is added in the toluene (10ml), to wherein adding morpholine (362 μ l), Tripotassium phosphate (1.03g), three (dibenzalacetones), two palladiums (0) (63mg) and 2-(dicyclohexyl phosphino-) biphenyl (97mg).Under argon gas atmosphere, reaction soln was stirred 24 hours down at 80 ℃, to wherein adding morpholine (362 μ l), Tripotassium phosphate (1.03g), three (dibenzalacetones), two palladiums (0) (63mg) and 2-(dicyclohexyl phosphino-) biphenyl (97mg).Mixture was stirred 24 hours down at 80 ℃.After cooling, water is poured in the reaction soln, and used the ethyl acetate extraction mixture.Organic layer washs with saturated brine, and uses dried over sodium sulfate.Solvent removed by evaporation at reduced pressure.(elutriant: normal hexane/chloroform=2/1) purifying obtains title compound (0.62g) to resistates with silica gel column chromatography.
APCI-MS M/Z：296[M+H] +。
Reference example 97:3-(benzyloxy)-6-tetramethyleneimine-1-yl pyridines-2-nitrile
3-(the benzyloxy)-6-bromopyridine-2-nitrile (2.00g) and the tetramethyleneimine (3.46ml) that obtain in the reference example 92 are handled with the mode that is similar to reference example 96, obtained title compound (1.30g).
APCI-MS M/Z：280[M+H] +。
Reference example 98:3-(benzyloxy)-6-(2-methoxyethoxy) pyridine-2-nitrile
Figure A20048000194101953
3-(the benzyloxy)-6-bromopyridine-2-nitrile (100mg) that obtains in the reference example 92 is added in the toluene (2ml), to wherein add cesium carbonate (169mg), acid chloride (II) (1.6mg), 2-(di-t-butyl phosphino-)-1,1 '-dinaphthalene (racemize) is (3.4mg) and 2-methoxyethanol (55 μ l).Under 70 ℃, stirred the mixture 24 hours.After cooling, water is poured in the reaction soln, and used the ethyl acetate extraction mixture.Organic layer washs with saturated brine, and uses dried over sodium sulfate.Solvent removed by evaporation at reduced pressure.Resistates obtains title compound (84mg) with silica gel column chromatography (elutriant: n-hexane/ethyl acetate=3/1 is 2/1 subsequently) purifying.
APCI-MS M/Z：285[M+H] +。
Reference example 99:3-(benzyloxy)-6-isopropoxy pyridine-2-nitrile
Figure A20048000194101961
3-(the benzyloxy)-6-bromopyridine-2-nitrile (2.00g) and the 2-propyl alcohol (3.96ml) that obtain in the reference example 92 are handled with the mode that is similar to reference example 98, obtained title compound (1.53g).
APCI-MS M/Z：269[M+H] +。
Reference example 100:6-(dimethylamino)-3-pyridone-2-nitrile
Figure A20048000194101962
3-(benzyloxy)-6-(dimethylamino) pyridine-2-nitrile (1.28g) that obtains in the reference example 93 is dissolved in the ethanol (50ml), to the palladium hydroxide/carbon (0.13g) that wherein adds 20%.Under the normal pressure hydrogen atmosphere, mixture was at room temperature stirred 2 hours.Remove by filter catalyzer.Concentrating under reduced pressure filtrate is also dry, obtains title compound (0.88g).
APCI-MS M/Z：164[M+H] +。
Reference example 101-105
Corresponding precursor compound is handled with the mode that is similar to reference example 100, obtained following compound.
Table 81
Reference example 106-111
Corresponding precursor compound is handled with the mode that is similar to reference example 23, obtained following compound.
Table 82
Figure A20048000194101981
Reference example 112:3-amino-N-(5-chloropyridine-2-yl)-5-(dimethylamino) furo [3,2-b] pyridine-2-carboxamide
With N-(5-chloropyridine-2-yl)-2-{[2-cyano group-6-(dimethylamino) pyridin-3-yl that obtains in the reference example 106] the oxygen base } ethanamide (1.59g) is suspended in the trimethyl carbinol (50ml), to wherein adding potassium tert.-butoxide (54mg).Mixture heating up was refluxed 2 hours.After cooling, water is poured in the reaction soln, filtered the solid of collecting precipitation.Resulting solid obtains title compound (1.16g) with ether washing and dry.
APCI-MS M/Z：332/334[M+H] +。
Reference example 113-117
Corresponding precursor compound is handled with the mode that is similar to reference example 112, obtained following compound.
Table 83
Figure A20048000194102001
Reference example 118 and 119
Amino furo [3,2-b] the pyridine-2-carboxylic acids methyl esters of the 3-that obtains in corresponding carboxylic acid and the reference example 78 is handled with the mode that is similar to reference example 79, obtained following compound.
Table 84
Reference example 120:3-amino-4-chloro-N-(5-chloropyridine-2-yl) furo [3,2-c] pyridine-2-carboxamide
Figure A20048000194102012
(1) with hydrogen bromide/acetate of 25% to known 2-chloro-4-methoxyl group-3-nitrile (reference: M.Mittelback etc. in the document, Arch.Pharm., 1985,318,481-486) carry out demethylating reaction, obtain 2-chloro-3-cyano group-4 (1H)-pyridone solid crude product.
ESI-MS M/Z：153/155[M-H] -。
(2) 2-chloro-3-cyano group-4 (the 1H)-pyridone that obtains in above-mentioned (1) is handled with the mode that is similar to reference example 23, is obtained N-(5-chloropyridine-2-yl)-2-[(2-chloro-3-cyanopyridine-4-yl) the oxygen base] the ethanamide solid crude product.
APCI-MS M/Z：323/325[M+H] +。
(3) with N-(5-chloropyridine-2-the yl)-2-[(2-chloro-3-cyanopyridine-4-yl that obtains in above-mentioned (2)) the oxygen base] ethanamide handles with the mode that is similar to reference example 112, obtains the title compound solid crude product.
APCI-MS M/Z：323/325[M+H] +。
Reference example 121:4-(benzyloxy)-2-bromopyridine-3-nitrile
Figure A20048000194102021
2-bromo-3-cyano group-4 (1H)-pyridone is handled with the mode that is similar to reference example 92, obtained title compound.
APCI-MS M/Z：289/291[M+H] +。
Reference example 122:4-(benzyloxy)-2-(the third oxygen carbonyl) pyridine-3-nitrile
Figure A20048000194102022
4-(the benzyloxy)-2-bromopyridine-3-nitrile (500mg) that obtains in the reference example 121 is dissolved in N, in the dinethylformamide (10ml), at room temperature to wherein adding 1-propyl alcohol (20ml) and triethylamine (410 μ l), with the mixture argon replaces.Add 1 in reaction soln, two (diphenyl phosphine) propane (114mg) of 3-and acid chloride (62mg) are replaced with the mixture degassing and with carbon monoxide.Mixture was stirred 19.5 hours down at 90 ℃ under carbon monoxide atmosphere, the dilute with water reaction soln, and use chloroform extraction.The organic layer dried over sodium sulfate, solvent evaporated under reduced pressure.Resistates silica gel column chromatography (elutriant: n-hexane/ethyl acetate=4/1 then is 1/1) purifying with being obtained obtains title compound (200mg).
APCI-MS M/Z：297[M+H] +。
Reference example 123:4-hydroxyl-2-(the third oxygen carbonyl) pyridine-3-nitrile
Figure A20048000194102023
4-(benzyloxy)-2-(the third oxygen carbonyl) pyridine-3-nitrile (199mg) that obtains in the reference example 122 is handled with the mode that is similar to reference example 100, obtained title compound (149mg).
APCI-MS M/Z：207[M+H] +。
Reference example 124:N-(5-chloropyridine-2-yl)-2-[(2-third oxygen carbonyl-3-cyanopyridine-4-yl) oxygen base] ethanamide
Figure A20048000194102031
4-hydroxyl-2-(the third oxygen carbonyl) pyridine-3-nitrile (145mg) that obtains in the reference example 123 is handled with the mode that is similar to reference example 23, obtained title compound (67.3mg).
APCI-MS M/Z：375/377[M+H] +。
Reference example 125:3-amino-N-(5-chloropyridine-2-yl)-4-(the third oxygen carbonyl) furo [3,2-c] pyridine-2-carboxamide
With N-(5-chloropyridine-2-the yl)-2-[(2-third oxygen carbonyl-3-cyanopyridine-4-yl that obtains in the reference example 124) the oxygen base] ethanamide (65mg) handles with the mode that is similar to reference example 112, obtains title compound (68mg).
APCI-MS M/Z：375/377[M+H] +。
EXPERIMENTAL EXAMPLE 1: to the restraining effect of activatory blooc coagulation factor X
The preparation method of substrate solution is as follows: with concentration is that the chromogenic substrate S-2222 of 0.625mM (final concentration 0.5mM) is dissolved in the Tris damping fluid (pH8.4) that comprises 200mM sodium-chlor and 0.1% bovine serum albumin(BSA).In addition test compound is dissolved in the damping fluid that comprises 10% methyl-sulphoxide and the preparation test compound solution.Test compound solution (25 μ l) is added in the substrate solution (200 μ l).In control group, the damping fluid that uses 25 μ l to comprise 10% methyl-sulphoxide replaces test compound solution.
At 37 ℃ down after pre-warm 3 minutes, 25 μ l are dissolved in people FXa in the damping fluid with 0.5U/ml concentration, and (Enzyme Research Laboratories Inc.) is added to the reaction mixture (final concentration of FXa: begin reaction 0.05U/ml).At 37 ℃ down in 5 minutes the process of reaction, go up the absorbancy at continuous monitoring 405nm place at 96 hole microtest plate readers (Spectra MAX250, Molecular Devices), and with the increase of absorbancy as the active index of FXa.Active for the FXa inhibition of evaluation test compound, (GraphPad Prism, GraphPad Software Inc.) calculate test compound and compare with control group operational analysis software, and the FXa activity is had 50% inhibiting concentration (IC 50Value).Below table 85 shown an example among the result.
Table 85
Embodiment IC 50(nM)
36 10.8
The shown 50% inhibition concentration (IC that goes out of The compounds of this invention 50Value) less than 1Mm, and the shown IC that goes out of wherein preferred compound 50Value is less than 20nM.Therefore, compound exhibits of the present invention has gone out the fabulous restraining effect to activatory blooc coagulation factor X.
Commercial Application
The compound of general formula (I) or the little and safety of its pharmaceutically acceptable salt toxicity have fabulous inhibitory action to the blooc coagulation factor X that activates. Therefore, compound (I) can be with acting on the medicament that prevents and treat the disease that is caused by thrombus or embolus.

Claims (27)

1, a kind of general formula (I) condense furan compound:
Figure A2004800019410002C1
Wherein, ring:
Figure A2004800019410002C2
Be
Figure A2004800019410002C3
Figure A2004800019410002C4
Perhaps
Figure A2004800019410002C5
Ring X is:
Figure A2004800019410002C6
Figure A2004800019410002C7
Perhaps
Y is the optional amino that replaces; The optional cycloalkyl that replaces; The optional aryl that replaces; The optional saturated heterocyclyl that replaces; The perhaps optional unsaturated heterocycle base that replaces;
A is a singly-bound; The optional alkylidene group that is replaced by the oxo base; Alkene support base; Alkenylene; Perhaps Sauerstoffatom;
R 1A, R 1BBe identical or different groups, the hydrogen of respectively doing for oneself; Halogen; Alkyl; Haloalkyl; Alkoxyl group; Cyano group; Nitro; The perhaps optional amino that replaces;
R 1CBe hydrogen, alkyl or halogen;
R 2A, R 2BBe identical or different groups, the hydrogen of respectively doing for oneself; Halogen; The optional alkyl that replaces; The optional alkoxyl group that replaces; The optional amino that replaces; Nitro; Cyano group; Hydroxyl; Carboxyl; The optional carbalkoxy that replaces; The optional formamyl that replaces; The carbonyl that the saturated heterocyclyl that is optionally substituted replaces; The optional saturated heterocyclyl that replaces; Aryl; The perhaps optional unsaturated heterocycle base that replaces;
R 3Be hydrogen or alkyl; And
R 4Be hydrogen or alkyl,
Perhaps its pharmacy acceptable salt.
2, according to the furan compound that condenses of claim 1, wherein encircle:
Be
Figure A2004800019410003C2
Figure A2004800019410003C3
Perhaps
Definition is identical in symbol wherein and the claim 1,
Perhaps its pharmacy acceptable salt.
3, according to the furan compound that condenses of claim 1 or 2, wherein encircle:
Figure A2004800019410003C5
Be
Figure A2004800019410004C1
Perhaps
Figure A2004800019410004C2
Definition is identical in symbol wherein and the claim 1,
Perhaps its pharmacy acceptable salt.
4, according to claim 1-3 any one condense furan compound, wherein Y is the optional cycloalkyl that replaces or the optional saturated heterocyclyl that replaces, perhaps its pharmacy acceptable salt.
5, according to claim 1-4 any one condense furan compound, be to be selected from the optional alkyl that replaces wherein to the substituting group in the definition of Y " the optional cycloalkyl that replaces "; The optional formamyl that replaces; The carbonyl that the saturated heterocyclyl that is optionally substituted replaces; The optional amino that replaces; With a kind of group of the optional saturated heterocyclyl that replaces, perhaps its pharmacy acceptable salt.
6, according to claim 1-5 any one condense furan compound, be a kind of group that is selected from following group to the substituting group in the definition of Y " the optional cycloalkyl that replaces " wherein: the group that (1) is selected from the optional acyl group that replaces, carbalkoxy and the optional alkyl that replaces choose the amino of replacement; (2) group that is selected from optional acyl group that replaces and the optional alkyl that replaces is chosen the aminoalkyl group that replaces wantonly; (3) alkyl that is optionally substituted is chosen the formamyl that replaces wantonly; (4) carbonyl that is replaced by saturated heterocyclyl; (5) the optional saturated heterocyclyl that replaces, perhaps its pharmacy acceptable salt.
7, according to the furan compound that condenses of claim 5 or 6, wherein saturated heterocyclyl is 4 yuan of-7 yuan of saturated heterocyclyls, and this heterocyclic radical comprises 1-4 the heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, perhaps its pharmacy acceptable salt.
8, according to claim 5-7 any one condense furan compound, wherein saturated heterocyclyl is a kind of group that is selected from imidazolidyl, pyrazolidyl, piperidyl, piperidino-(1-position only), piperazinyl, (2-or 3-) morpholinyl, morpholino, thio-morpholinyl, thiomorpholine generation, high piperazinyl, homopiperidinyl, high-piperidine sub-base and pyrrolidyl, perhaps its pharmacy acceptable salt.
9, according to claim 1-6 any one condense furan compound, wherein to the substituting group in the definition of Y " the optional cycloalkyl that replaces " be: a kind of group that (1) is selected from aminoalkyl group, alkoxycarbonyl amido alkyl and amidoalkyl that acyl group, carbalkoxy, alkyl, aminoalkyl group, alkyl replace choose the amino of replacement; (2) by the amino alkyl that replaces, wherein amino choosing wantonly replaced by alkyl; (3) optional by alkyl or aminoalkyl group one replacement or dibasic formamyl, wherein aminoalkyl group can be replaced by alkyl; (4) be selected from a kind of group of pyrrolidyl carbonyl, piperidino carbonyl, piperazinyl carbonyl, morpholino carbonyl, homopiperidinyl carbonyl and high piperazinyl carbonyl; Perhaps (5) are selected from and choose the pyrrolidyl that is replaced by the oxo base, optional piperidyl, optional piperazinyl, optional morpholino base, optional homopiperidinyl and the saturated heterocyclyl of choosing the high piperazinyl that is replaced by the oxo base wantonly, perhaps its pharmacy acceptable salt that is replaced by the oxo base that is replaced by the oxo base that is replaced by the oxo base that is replaced by the oxo base wantonly.
10, according to claim 1-6 any one condense furan compound, be the optional pyrrolidyl that is replaced by the oxo base wherein to the substituting group in the definition of Y " the optional cycloalkyl that replaces "; The optional morpholino base that is replaced by the oxo base; The dialkyl amido formyl radical; The pyrrolidyl carbonyl; By alkyl and the disubstituted amino of amidoalkyl; Perhaps dialkyl amido, perhaps its pharmacy acceptable salt.
11, according to claim 1-3 any one condense furan compound, wherein Y is aryl or the undersaturated heterocyclic radical that the formamyl that is optionally substituted replaces, perhaps its pharmacy acceptable salt.
12, according to claim 1-11 any one condense furan compound, wherein A is singly-bound or methylene radical, perhaps its pharmacy acceptable salt.
13, according to claim 1-4 any one condense furan compound, wherein A is singly-bound or methylene radical, Y is optional unsaturated heterocycle base or the saturated heterocyclyl that is replaced by alkyl, perhaps its pharmacy acceptable salt.
14, according to claim 1-3 any one condense furan compound, wherein A is a tetramethylene, Y is the optional saturated heterocyclyl that replaces, perhaps its pharmacy acceptable salt.
15, according to claim 1-14 any one condense furan compound, wherein R 1A, R 1BBe identical or different groups, the hydrogen of respectively doing for oneself, halogen or alkyl, perhaps its pharmacy acceptable salt.
16, according to claim 1-15 any one condense furan compound, wherein R 2A, R 2BBe identical or different groups, the hydrogen of respectively doing for oneself; Halogen; The optional alkyl that replaces; The optional alkoxyl group that replaces; The optional amino that replaces; Cyano group; Carboxyl; Carbalkoxy; The optional formamyl that replaces; The carbonyl that is replaced by saturated heterocyclyl; Perhaps saturated heterocyclyl, perhaps its pharmacy acceptable salt.
17, according to the furan compound that condenses of claim 16, wherein saturated heterocyclyl is 4 yuan of-7 yuan of saturated heterocyclyls, and this heterocyclic radical comprises 1-4 the heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, perhaps its pharmacy acceptable salt.
18, according to claim 1-17 any one condense furan compound, wherein R 2A, R 2BIt is identical or different groups; respectively do for oneself hydrogen, fluorine, chlorine, bromine, methyl, methylol, methoxyl group, amino, sulfonyloxy methyl amino, kharophen, t-butoxycarbonyl amino, dimethylamino, cyano group, carboxyl, methoxycarbonyl, ethoxycarbonyl, methoxyl group, oxyethyl group, isopropoxy, methoxyethoxy, formyl-dimethylamino, N-methyl-N-(2-methoxyethyl) formamyl, pyrrolidyl, pyrrolidyl carbonyl, morpholino carbonyl or morpholino, perhaps its pharmacy acceptable salt.
19, according to claim 1-18 any one condense furan compound, wherein R 3Be hydrogen, perhaps its pharmacy acceptable salt.
20, according to claim 1-19 any one condense furan compound, wherein R 4Be hydrogen, perhaps its pharmacy acceptable salt.
21, according to claim 1-20 any one condense furan compound, wherein encircle X and be
Figure A2004800019410006C1
Figure A2004800019410006C2
Perhaps
Figure A2004800019410006C3
Definition is identical in symbol wherein and the claim 1,
Perhaps its pharmacy acceptable salt.
22,, wherein encircle X and be according to the furan compound that condenses of claim 21
Perhaps
Figure A2004800019410007C2
Definition is identical in symbol wherein and the claim 1,
Perhaps its pharmacy acceptable salt.
23, according to claim 1-22 any one condense furan compound, this compound is selected from following compound:
(1) 5-amino-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(2) 6-amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(3) N-(4-chloro-phenyl-)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(4) amino N-(5-chloropyridine-2-yl)-5-[(methylsulfonyl)]-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-2-carboxamide,
(5) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-5-carboxylic acid,
(6) N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-base-cyclohexyl) carbonyl] amino furo [3,2-c] pyridine-2-carboxamide,
(7) N-(5-chloropyridine-2-yl)-5-(methylol)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(8) N-(5-chloropyridine-2-yl)-5-methoxyl group-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(9) N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-base-cyclohexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(10) N-(5-chloropyridine-2-yl)-5-methoxyl group-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(11) N-(4-chloro-phenyl-)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(12) 5-amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(13) 5-(kharophen)-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(14) N-(5-chloropyridine-2-yl)-5-fluoro-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(15) 5-chloro-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(16) N-(5-chloropyridine-2-yl)-5-methyl-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(17) N 2-(5-chloropyridine-2-yl)-N 5, N 5-dimethyl-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-2, the 5-diformamide,
(18) 5-(kharophen)-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(19) (2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-6-yl)-t-butyl carbamate,
(20) amino N-(5-chloropyridine-2-yl)-5-[(methylsulfonyl)]-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(21) N-(4-chloro-phenyl-)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl)-cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(22) carbonyl N-(5-chloropyridine-2-yl)-3-{[(1-pyridin-4-yl piperidin-4-yl)] amino } furo [3,2-b] pyridine-2-carboxamide,
(23) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(24) [2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-6-yl] t-butyl carbamate,
(25) 6-amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(26) 6-amino-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(27) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylic acid,
(28) N 2-(5-chloropyridine-2-yl)-N 5, N 5-dimethyl-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2, the 5-diformamide,
(29) N-(5-chloropyridine-2-yl)-5-(morpholine-4-base carbonyl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(30) (2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-5-yl)-t-butyl carbamate,
(31) N-(5-chloropyridine-2-yl)-5-methyl-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(32) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-5-carboxylate methyl ester,
(33) 5-bromo-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(34) amino N-(5-chloropyridine-2-yl)-5-[(methylsulfonyl)]-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(35) N-(4-chloro-phenyl-)-3-({ [trans-4-(dimethylamino) cyclohexyl]-carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(36) N-(5-chloropyridine-2-yl)-5-cyano group-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(37) N-(5-chloropyridine-2-yl)-5-fluoro-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(38) N 2-(5-chloropyridine-2-yl)-N 5-(2-methoxyethyl)-N 5-methyl-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2, the 5-diformamide,
(39) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(40) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino)-5-(tetramethyleneimine-1-base carbonyl) furo [3,2-b] pyridine-2-carboxamide,
(41) [2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-yl] t-butyl carbamate,
(42) 5-bromo-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(43) N-(5-chloropyridine-2-yl)-5-(morpholine-4-base carbonyl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(44) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-5-methoxyl group furo [3,2-b] pyridine-2-carboxamide,
(45) 5-chloro-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl) carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(46) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylic acid,
(47) N-(5-chloropyridine-2-yl)-5-cyano group-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(48) N-(5-chloropyridine-2-yl)-5-cyano group-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(49) N-(5-chloropyridine-2-yl)-5-(methylol)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(50) N-(5-chloropyridine-2-yl)-5-methoxyl group-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(51) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino)-5-(tetramethyleneimine-1-base carbonyl) furo [3,2-b] pyridine-2-carboxamide,
(52) N-(5-chloropyridine-2-yl)-5-methyl-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(53) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-5-methyl furan [3,2-b] pyridine-2-carboxamide also,
(54) 5-chloro-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(55) N 2-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-N 5, N 5-dimethyl furan is [3,2-b] pyridine-2 also, the 5-diformamide,
(56) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylate methyl ester,
(57) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(58) 5-amino-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(59) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(60) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-{[5-(3-oxo morpholine-4-yl) pentanoyl] amino } furo [3,2-b] pyridine-5-carboxylic acid,
(61) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(62) 6-chloro-N-(5-chloropyridine-2-yl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(63) 5-chloro-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(64) N 2-(5-chloropyridine-2-yl)-N 5, N 5-dimethyl-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2, the 5-diformamide,
(65) 6-(kharophen)-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(tetramethyleneimine-1-basic ring hexyl) carbonyl] amino } furo [3,2-b] pyridine-2-carboxamide,
(66) [2-{[(5-chloropyridine-2-yl) amino] carbonyl }-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-6-yl] t-butyl carbamate,
(67) 6-chloro-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(68) N-(4-aminomethyl phenyl)-3-({ [trans-4-(3-oxo morpholine-4-yl)-cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(69) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-6-carboxylic acid,
(70) N-(5-chloropyridine-2-yl)-3-{[5-(3-oxo morpholine-4-yl) pentanoyl] amino } furo [3,2-b] pyridine-2-carboxamide,
(71) 5-(kharophen)-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(72) N-(4-chloro-phenyl-)-3-{[(trans-4-morpholine-4-basic ring hexyl)-carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(73) 5-bromo-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(74) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino) furo [2,3-b] pyridine-2-carboxamide,
(75) 3-[({ trans-4-[[3-(kharophen) propyl group] (methyl) amino]-cyclohexyl carbonyl) amino]-N-(5-chloropyridine-2-yl) furo [3,2-b] pyridine-2-carboxamide,
(76) trans-N '-(2-{[(5-chloropyridine-2-yl) amino] carbonyl } furo [3,2-b] pyridin-3-yl)-N, N-dimethyl cyclohexane-1, the 4-diformamide,
(77) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(tetramethyleneimine-1-base carbonyl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(78) 2-{ ((5-chloropyridine-2-yl) amino] carbonyl }-3-[({ is trans-the 4-[(dimethylamino) carbonyl] cyclohexyl carbonyl) amino] furo [3,2-b]-pyridine-5-carboxylic acid,
(79) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-({ [trans-4-(tetramethyleneimine-1-base carbonyl) cyclohexyl] carbonyl } amino) furo [3,2-b]-pyridine-5-carboxylate methyl ester,
(80) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-the trans 4-[(dimethylamino of 3-[({) carbonyl] cyclohexyl } carbonyl) amino] furo [3,2-b] pyridine-5-carboxylate methyl ester,
(81) amino 2-{[(5-chloropyridine-2-yl)] carbonyl }-3-({ [trans-4-(tetramethyleneimine-1-base carbonyl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-5-carboxylic acid,
(82) N 2-(5-chloropyridine-2-yl)-3-[({ is trans-the 4-[(dimethylamino)-carbonyl] cyclohexyl } carbonyl) amino]-N 5-(2-methoxyethyl)-N 5-methyl furan is [3,2-b] pyridine-2 also, the 5-diformamide,
(83) N 2-(5-chloropyridine-2-yl)-N 5-(2-methoxyethyl)-N 5-methyl-3-({ [trans-4-(tetramethyleneimine-1-base carbonyl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2, the 5-diformamide,
(84) N-(5-chloropyridine-2-yl)-5-tetramethyleneimine-1-base-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(85) N-(5-chloropyridine-2-yl)-5-morpholine-4-base-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(86) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino)-5-tetramethyleneimine-1-base furo [3,2-b] pyridine-2-carboxamide,
(87) N-(5-chloropyridine-2-yl)-5-(dimethylamino)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(88) N-(5-chloropyridine-2-yl)-5-morpholine-4-base-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(89) N-(5-chloropyridine-2-yl)-4-(2-methoxyethoxy)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-c] pyridine-2-carboxamide,
(90) N-(5-chloropyridine-2-yl)-5-(2-methoxyethoxy)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(91) N-(5-chloropyridine-2-yl)-5-(tetramethyleneimine-1-base carbonyl)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(92) N-(5-chloropyridine-2-yl)-4-(2-methoxyethoxy)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(93) N-(5-chloropyridine-2-yl)-4-methoxyl group-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-c] pyridine-2-carboxamide,
(94) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-5-tetramethyleneimine-1-base furo [3,2-b] pyridine-2-carboxamide,
(95) N 2-(5-chloropyridine-2-yl)-N 5-(2-methoxyethyl)-N 5-methyl-3-{[(is trans-4-tetramethyleneimine-1-basic ring hexyl) and carbonyl] amino } furo [3,2-b] pyridine-2, the 5-diformamide,
(96) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(97) N-(5-chloropyridine-2-yl)-5-(dimethylamino)-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(98) N-1H-indoles-6-base-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(99) N-(5-chloropyridine-2-yl)-4-methoxyl group-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(100) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino)-5-tetramethyleneimine-1-base furo [3,2-b] pyridine-2-carboxamide,
(101) N-(5-chloropyridine-2-yl)-5-isopropoxy-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(102) N-(5-chloropyridine-2-yl)-5-isopropoxy-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(103) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino) cyclohexyl] carbonyl } amino)-5-(2-methoxyethoxy)-furo [3,2-b] pyridine-2-carboxamide,
(104) N-(5-chloropyridine-2-yl)-5-morpholine-4-base-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(105) N-(5-chloropyridine-2-yl)-5-(dimethylamino)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(106) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-5-morpholine-4-base furo [3,2-b] pyridine-2-carboxamide,
(107) N-(5-chloropyridine-2-yl)-5-(2-methoxyethoxy)-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(108) N-(5-chloropyridine-2-yl)-5-(dimethylamino)-3-({ [trans-4-(dimethylamino) cyclohexyl] carbonyl } amino) furo [3,2-b] pyridine-2-carboxamide,
(109) N-(5-chloropyridine-2-yl)-3-({ [trans-4-(dimethylamino)-cyclohexyl] carbonyl } amino)-5-isopropoxy furo [3,2-b] pyridine-2-carboxamide,
(110) N-1H-indoles-6-base-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-b] pyridine-2-carboxamide,
(111) N-(5-chloropyridine-2-yl)-4-cyano group-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-c] pyridine-2-carboxamide,
(112) N-(5-chloropyridine-2-yl)-4-methyl-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(113) N-(5-chloropyridine-2-yl)-4-cyano group-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(114) N-(5-chloropyridine-2-yl)-4-methyl-3-({ [trans-4-(2-oxo-pyrrolidine-1-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide,
(115) 4-chloro-N-(5-chloropyridine-2-yl)-3-({ [trans-4-(3-oxo morpholine-4-yl) cyclohexyl] carbonyl } amino) furo [3,2-c] pyridine-2-carboxamide and
(116) N-(5-chloropyridine-2-yl)-4-methyl-3-{[(trans-4-tetramethyleneimine-1-basic ring hexyl) carbonyl] amino furo [3,2-c] pyridine-2-carboxamide,
Perhaps its pharmacy acceptable salt.
24, the compound of general formula (II):
Figure A2004800019410015C1
Wherein definition identical in symbol and the claim 1, perhaps its salt.
25, the compound of general formula (VI):
Wherein definition identical in symbol and the claim 1, perhaps its salt.
26, the compound of general formula (IV):
Figure A2004800019410015C3
Wherein R is a hydrogen, C 1-4Alkyl or carboxyl-protecting group, other symbols as defined in claim 1, perhaps its salt.
27, the compound of general formula (IX):
Wherein R is a hydrogen, C 1-4Alkyl or carboxyl-protecting group, other symbols as defined in claim 1, perhaps its salt.
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